N2-phenyl-pyrido[3,4- d]pyrimidine-2, 8-diamine derivatives and their use as mps1 inhibitors

ABSTRACT

The present invention relates to compounds of formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and R 4  are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

This application is a continuation of U.S. Ser. No. 15/121,432, filedAug. 25, 2016, which is the U.S. National Stage of International PatentApplication No. PCT/GB2015/050590, filed Feb. 27, 2015, which claims thebenefit of and priority to Great Britain Patent Application No.1403536.4, filed Feb. 28, 2014.

INTRODUCTION

The present invention relates to compounds that inhibit the spindlecheckpoint function of monopolar spindle 1 (Mps1—also known as TTK)kinases, either directly or indirectly via interaction with the Mps1kinase itself. In particular, the present invention relates to compoundsfor use as therapeutic agents for the treatment and/or prevention ofproliferative diseases, such as cancer. The present invention alsorelates to processes for the preparation of these compounds, and topharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Cancer is caused by uncontrolled and unregulated cellular proliferation.Precisely what causes a cell to become malignant and proliferate in anuncontrolled and unregulated manner has been the focus of intenseresearch over recent decades. This research has led to the targeting ofsurveillance mechanisms, such as those responsible for regulating thecell cycle, with anticancer agents. For example, published patentapplication WO 2009/103966 (CANCER RESEARCH TECHNOLOGY LIMITED) relatesto the inhibition of checkpoint kinase 1 (CHK1) kinase function, withbicyclylaryl-aryl-amine compounds, in the treatment of cancer.

The main role of the cell cycle is to enable error-free DNA replication,chromosome segregation and cytokinesis. Surveillance mechanisms, theso-called checkpoint pathways, monitor passage through mitosis atseveral stages. One of the best characterised is the spindle assemblycheckpoint that prevents anaphase onset until the appropriate tensionand attachment across kinetochores is achieved (HARDWICK K G, 1998, “Thespindle checkpoint”, Trends Genet 14, 1-4). The majority of proteinsinvolved in the checkpoint exert their functions through protein bindinginteractions with the involvement of only a small number of kinases(MUSACCHIO A et al, 2007, “The spindle-assembly checkpoint in space andtime”, Nature Reviews, Molecular and Cell Biology, 8, 379-393). Amitotic checkpoint complex (MCC) that contains three checkpoint proteins(Mad2, BubR1/Mad3, Bub3) and the APC/C co-factor, CDC20, concentrates atthe kinetochores and acts as a spindle checkpoint effector. Other coreproteins required to amplify the checkpoint signal include Mad1 and thekinases Bub1, Mps1 (also known as TTK) and Aurora-B (MUSACCHIO,referenced above).

One of the first components of the spindle assembly checkpoint signal,identified by a genetic screen in budding yeast, was dubbed Mps1(monopolar spindle 1) for the monopolar spindles produced by Mps1 mutantcells (WEISS E, 1996, “The Saccharomyces cerevisiae spindle pole bodyduplication gene MPS1 is part of a mitotic checkpoint”, J Cell Biol 132,111-123), however, it still remains one of the least studied checkpointcomponents in higher eukaryotes. Subsequently, the Mps1 gene was shownto encode an essential dual-specificity kinase (LAUZE et al, 1995,“Yeast spindle pole body duplication gene MPS1 encodes an essential dualspecificity protein kinase”, EMBO J 14, 1655-1663 and also POCH et al,1994, “RPK1, an essential yeast protein kinase involved in theregulation of the onset of mitosis, shows homology to mammaliandual-specificity kinases”, Mol Gen Genet 243, 641-653) conserved fromyeast to humans (MILLS et al, 1992, “Expression of TTK, a novel humanprotein kinase, is associated with cell proliferation”, J Biol Chem 267,16000-16006). Mps1 activity peaks at the G₂/M transition and is enhancedupon activation of the spindle checkpoint with nocodazole (STUCKE et al,2002, “Human Mps1 kinase is required for the spindle assembly checkpointbut not for centrosome duplication”, EMBO J 21, 1723-1732 and also LIUet al, 2003, “Human MPS1 kinase is required for mitotic arrest inducedby the loss of CENP-E from kinetochores”, Mol Biol Cell 14, 1638-1651).The autophosphorylation of Mps1 at Thr676 in the activation loop hasbeen identified and is essential for Mps1 function (MATTISON et al,2007, “Mps1 activation loop autophosphorylation enhances kinaseactivity”, J Biol Chem 282, 30553-30561).

Given the importance of Mps1 in spindle checkpoint activation, thedevelopment of Mps1 inhibitors would be an asset, not only as a tool tofurther investigate its cell cycle-related functions, but also as a formof anticancer treatment. The first generation inhibitors of Mps1 havebeen described. Cincreasin, caused chromosome mis-segregation and deathin yeast cells (DORER et al, 2005, “A small-molecule inhibitor of Mps1blocks the spindle-checkpoint response to a lack of tension on mitoticchromosomes”, Curr Biol 15, 1070-1076) and SP600125, a JNK (c-Junamino-terminal kinase) inhibitor, also disrupts spindle checkpointfunction in a JNK-independent manner via the inhibition of Mps1 (SCHMIDTet al, 2005, “Ablation of the spindle assembly checkpoint by a compoundtargeting Mps1”, EMBO Rep 6, 866-872). Recently, three small moleculeinhibitors of Mps1 were identified (KWIATOWSKI et al, 2010,“Small-molecule kinase inhibitors provide insight into Mps1 cell cyclefunction”, Nat Chem Biol 6, 359-368; HEWITT et al, 2010, “Sustained Mps1activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2core complex”, J Cell Biol 190, 25-34; and SANTAGUIDA et al, 2010,“Dissecting the role of MPS1 in chromosome biorientation and the spindlecheckpoint through the small molecule inhibitor reversine”, J Cell Biol190, 73-87). Chemical inhibition of Mps1 induced premature mitotic exit,gross aneuploidy and death to human cancer cell lines (KWIATOWSKI,above). Mps1 inhibitors AZ3146 and reversine, severely impairedrecruitment of Mad1, Mad2 and CENP-E to kinetochores (HEWITT, andSANTAGUIDA, above).

Dysregulation of the mitotic checkpoint is recognised as a feature ofthe malignant transformation process. Mitotic checkpoint dysfunction intumors provides an opportunity for developing a therapeutic strategyusing small molecules. This is based on the proposition thatpharmacologic disruption of an already compromised mitotic checkpointmay selectively sensitize tumors. This observation has led to thehypothesis that inhibition of Mps1 may be of therapeutic benefit.

It is an objective of the present invention to provide compounds thatare potent inhibitors of Mps1.

It is a further objective to provide compounds that possess one or moreadvantageous pharmaceutical properties, such as, for example,advantageous cell and/or in vivo potency, good solubility and/or one ormore advantageous DMPK properties (for example, a favourable metabolicstability profile, favourable Cyp inhibition, a favourable hERG profile,a favourable clearance profile, a favourable volume of distributionetc.).

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, as defined herein.

In another aspect, the present invention provides a pharmaceuticalcomposition which comprises a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in therapy.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a proliferative condition.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof cancer. In a particular embodiment, the cancer is a human cancer.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the productionof a Mps1 kinase inhibitory effect.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofa proliferative condition.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofcancer. Suitably, the medicament is for use in the treatment of humancancers.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the production ofan Mps1 kinase inhibitory effect.

In another aspect, the present invention provides a method of inhibitingMps1 kinase in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibitingcell proliferation in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating aproliferative disorder in a patient in need of such treatment, saidmethod comprising administering to said patient a therapeuticallyeffective amount of a compound as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a method of treatingcancer in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein.

The present invention further provides a method of synthesising acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof,obtainable by, or obtained by, or directly obtained by a method ofsynthesis as defined herein.

In another aspect, the present invention provides novel intermediatesdefined herein which are suitable for use in any one of the syntheticmethods set out herein.

Preferred, suitable, and optional features of any one particular aspectof the present invention are also preferred, suitable, and optionalfeatures of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings set out below.

It is to be appreciated that references to “treating” or “treatment”include prophylaxis as well as the alleviation of established symptomsof a condition. “Treating” or “treatment” of a state, disorder orcondition therefore includes: (1) preventing or delaying the appearanceof clinical symptoms of the state, disorder or condition developing in ahuman that may be afflicted with or predisposed to the state, disorderor condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition, (2) inhibitingthe state, disorder or condition, i.e., arresting, reducing or delayingthe development of the disease or a relapse thereof (in case ofmaintenance treatment) or at least one clinical or subclinical symptomthereof, or (3) relieving or attenuating the disease, i.e., causingregression of the state, disorder or condition or at least one of itsclinical or subclinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. References to individual alkyl groups suchas “propyl” are specific for the straight chain version only andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. For example,“(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl andt-butyl. A similar convention applies to other radicals, for example“phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyland 2-phenylethyl.

The term “(m-nC)” or “(m-nC) group” used alone or as a prefix, refers toany group having m to n carbon atoms.

The term “alkylene” is used herein to refer to both straight andbranched chain alkylene linker groups. For example, references to(1-4C)alkylene groups include methylene (—CH₂—), ethylene (—CH₂—CH₂—),propylene (—CH₂—CH₂—CH₂—) and butylene (—CH₂—CH₂—CH₂—CH₂—), as well asbranched groups such as, for example, —CH(CH₃)—, —C(CH₃)₂— or—CH₂—CH(CH₃)—.

The term “(3-8C)cycloalkyl” means a hydrocarbon ring containing from 3to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or bicycle[2.2.2]octane, bicycle[2.1.1]hexane,bicycle[1.1.1]pentane and bicyclo[2.2.1]heptyl.

The term “(1-8C)heteroalkyl” refers to an alkyl chain comprising 1-8carbon atoms which additionally comprises one, two or three heteroatomspresent within the alkyl chain which are selected from the groupconsisting of N, O, or S.

The term “halo” refers to fluoro, chloro, bromo and iodo.

The term “fluoroalkyl” is used herein to refer to an alkyl group inwhich one or more hydrogen atoms have been replaced by fluorine atoms.Examples of fluoroalkyl groups include —CHF₂, —CH₂CF₃, or perfluoroalkylgroups such as —CF₃ or —CF₂CF₃.

The term “fluoroakoxy” is used herein to refer to an alkoxy group inwhich one or more hydrogen atoms have been replaced by fluorine atoms.Examples of fluoroalkoxy groups include —OCHF₂, —OCH₂CF₃, orperfluoroalkoxy groups such as —OCF₃ or —OCF₂CF₃.

The term “heterocyclyl”, “heterocyclic” or “heterocycle” means anon-aromatic saturated or partially saturated monocyclic, fused,bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclicheterocyclic rings contain from about 3 to 12 (suitably from 3 to 7)ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selectedfrom nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclescontain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in thering. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridgedring systems. Examples of heterocyclic groups include cyclic ethers suchas oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substitutedcyclic ethers. Heterocycles containing nitrogen include, for example,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl,tetrahydropyrazolyl, and the like. Typical sulfur containingheterocycles include tetrahydrothienyl, dihydro-1,3-dithiol,tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocyclesinclude dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for aheterocyclyl group which bears 1 or 2 oxo (═O) or thioxo (═S)substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3 to 7 memberedheterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl orhomopiperazinyl. As the skilled person would appreciate, any heterocyclemay be linked to another group via any suitable atom, such as via acarbon or nitrogen atom. However, reference herein to piperidino ormorpholino refers to a piperidin-1-yl or morpholin-4-yl ring that islinked via the ring nitrogen.

By “bridged ring systems” is meant ring systems in which two rings sharemore than two atoms, see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages 131-133, 1992.Examples of bridged heterocyclyl ring systems include,aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

By “spiro bi-cyclic ring systems” we mean that the two ring systemsshare one common spiro carbon atom, i.e. the heterocyclic ring is linkedto a further carbocyclic or heterocyclic ring through a single commonspiro carbon atom. Examples of spiro ring systems include6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane,2-azaspiro[3.3]heptanes, 2-oxa-6-azaspiro[3.3]heptanes,7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane,2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

“Heterocyclyl(m-nC)alkyl” means a heterocyclyl group covalently attachedto a (m-nC)alkylene group, both of which are defined herein.

The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-,or polycyclic ring incorporating one or more (for example 1-4,particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur. Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a 5- or6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, forexample a bicyclic structure formed from fused five and six memberedrings or two fused six membered rings. Each ring may contain up to aboutfour heteroatoms typically selected from nitrogen, sulfur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, moreusually up to 2, for example a single heteroatom. In one embodiment, theheteroaryl ring contains at least one ring nitrogen atom. The nitrogenatoms in the heteroaryl rings can be basic, as in the case of animidazole or pyridine, or essentially non-basic as in the case of anindole or pyrrole nitrogen. In general the number of basic nitrogenatoms present in the heteroaryl group, including any amino groupsubstituents of the ring, will be less than five.

Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl,pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl,5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl”also covers partially aromatic bi- or polycyclic ring systems wherein atleast one ring is an aromatic ring and one or more of the other ring(s)is a non-aromatic, saturated or partially saturated ring, provided atleast one ring contains one or more heteroatoms selected from nitrogen,oxygen or sulfur. Examples of partially aromatic heteroaryl groupsinclude for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl,dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl,2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl,indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Examples of five membered heteroaryl groups include but are not limitedto pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl,oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from:

a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;f) a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;g) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;h) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;i) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;j) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;k) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or2 ring heteroatoms;l) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or3 ring heteroatoms;m) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;n) a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ringcontaining 1, 2 or 3 ring heteroatoms; ando) a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ringcontaining 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl(e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine,and pyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinolinyl,isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl,chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl,benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl and pteridinyl groups.

“Heteroaryl(m-nC)alkyl” means a heteroaryl group covalently attached toa (m-nC)alkylene group, both of which are defined herein. Examples ofheteroaralkyl groups include pyridin-3-ylmethyl,3-(benzofuran-2-yl)propyl, and the like.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms. The term aryl includes both monovalent species anddivalent species. Examples of aryl groups include, but are not limitedto, phenyl, biphenyl, naphthyl and the like. In particular embodiment,an aryl is phenyl.

The term “aryl(m-nC)alkyl” means an aryl group covalently attached to a(m-nC)alkylene group, both of which are defined herein. Examples ofaryl-(m-nC)alkyl groups include benzyl, phenylethyl, and the like.

This specification also makes use of several composite terms to describegroups comprising more than one functionality. Such terms will beunderstood by a person skilled in the art. For exampleheterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted byheterocyclyl.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

The phrase “compound of the invention” means those compounds which aredisclosed herein, both generically and specifically.

Compounds of the Invention

In one aspect, the present invention provides a compound of formula Ishown below:

wherein:R₁ is selected from:

-   -   (i) a 5- or 6-membered heteroaryl optionally substituted with        one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),        -   wherein R_(a) and R_(b) are each independently selected from            H or (1-4C)alkyl, and wherein any alkyl moiety present in            the substituent group is optionally further substituted with            one or more substituents selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, 4-7-membered            heterocyclyl, NR_(c)R_(d), OR_(c), C(O)R_(c), C(O)OR_(c),            OC(O)R_(c), N(R_(d))OR_(c), C(O)N(R_(d))R_(c),            N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is 0, 1 or 2),            SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c) and            R_(d) are each independently selected from H or (1-4C)alkyl;            or        -   wherein the 5- or 6-membered heteroaryl is optionally fused            to a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the            fused ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(k)R_(l),            OR_(k), C(O)R_(k), C(O)OR_(k), OC(O)R_(k), N(R_(l))OR_(k),            C(O)N(R_(l))R_(k), N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p            is 0, 1 or 2), SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l),            wherein R_(k) and R_(l) are each independently selected from            H or (1-4C)alkyl,        -   and wherein any alkyl moiety present in the substituent            group is optionally further substituted with one or more            substituents selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-4C)alkyl, 4-7-membered heterocyclyl, NR_(m)R_(n),            OR_(m), C(O)R_(m), C(O)OR_(m), OC(O)R_(m), N(R_(n))OR_(m),            C(O)N(R_(n))R_(m), N(R_(n))C(O)R_(m), S(O)_(q)R_(m) (where q            is 0, 1 or 2), SO₂N(R_(n))R_(m), or N(R_(n))SO₂R_(m),            wherein R_(m) and R_(n) are each independently selected from            H or (1-4C)alkyl; or    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-4C)alkyl which is optionally substituted by halo or            (1-2C)alkoxy;        -   or R_(e) and R_(f) are linked such that, together with the            nitrogen atom to which they are attached, they form a 4-, 5-            or 6-membered heterocyclic ring, wherein said ring is            optionally substituted with one or more substituents            independently selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-4C)alkyl, NR_(g)R_(h), OR_(g), C(O)R_(g),            C(O)OR_(g), OC(O)R_(g), N(R_(h))OR_(g), C(O)N(R_(h))R_(g),            N(R_(h))C(O)R_(g), S(O)_(p)R_(h) (where p is 0, 1 or 2),            SO₂N(R_(h))R_(g), or N(R_(h))SO₂R_(g), wherein R_(g) and            R_(h) are each independently selected from H or (1-4C)alkyl;            R₂ is selected from hydrogen, fluoro, chloro, (1-3C)alkoxy            or (1-3C)fluoroalkoxy; and either:    -   (i) R₃ is selected from hydrogen or (1-3C)alkyl and R₄ is        selected from (1-6C)alkyl, (3-9C)cycloalkyl,        (3-9C)cycloalkyl-(1-4C)alkyl, aryl, aryl-(1-4C)alkyl,        heterocyclyl, heterocyclyl-(1-4C)alkyl, heteroaryl,        heteroaryl-(1-4C)alkyl, and wherein R₄ is optionally further        substituted by one or more substituents selected from hydroxy,        fluoro, chloro, cyano, CF₃, CHF₂, OCF₃, OCHF₂, (1-4C)alkyl,        NR_(o)R_(p), OR_(o), C(O)R_(o), C(O)OR_(p), OC(O)R_(o),        N(R_(p))OR_(o), C(O)N(R_(p))R_(o), N(R_(p))C(O)R_(o),        S(O)_(p)R_(o) (where p is 0, 1 or 2), SO₂N(R_(p))R_(o), or        N(R_(p))SO₂R_(o) or (3-6C)cycloalkyl,        (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or 6-membered heterocyclyl,        a 4, 5 or 6-membered heterocyclyl-(1-2C)alkyl, wherein R_(o) and        R_(p) are each independently selected from H or (1-4C)alkyl,        (3-6C)cycloalkyl or (3-6C)cycloalkyl-(1-4C)alkyl; or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-6- or 7-membered heterocyclic ring,        -   wherein said ring is optionally fused to a further 3-, 4-,            5- or 6-membered ring carbocyclic or heterocyclic ring, a 5-            or 6-membered heteroaryl ring or a phenyl ring to form a            bi-cyclic heterocyclic system, or        -   linked through a spiro carbon atom to a further 4-, 5- or            6-membered ring carbocyclic or heterocyclic ring to form a            spiro bicyclic ring system; and wherein the heterocyclic            ring, bicyclic ring system or spiro bicyclic ring system is            optionally substituted by one or more substituents            independently selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-4C)alkyl, NR_(i)R_(j), OR_(i), C(O)R_(i),            C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i), C(O)N(R_(j))R_(i),            N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q is 0, 1 or 2),            SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i), wherein R_(i) and            R_(j) are each independently selected from H or (1-4C)alkyl;            or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula I defined hereinwith the proviso that said compound is not one of the following:

-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   (4-(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)-6-methylpyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol.

Particular compounds of the invention include, for example, compounds ofthe formula I, or pharmaceutically acceptable salts or solvates thereof,wherein, unless otherwise stated, each of R₁, R₂, R₃, R₄ or R_(a-o) hasany of the meanings defined hereinbefore or in any one of paragraphs (1)to (58) hereinafter:—

(1) R₁ is selected from:

-   -   (i) a 5- or 6-membered heteroaryl optionally substituted with        one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),        -   wherein R_(a) and R_(b) are each independently selected from            H or (1-2C)alkyl, and wherein any alkyl moiety present in            the substituent group is optionally further substituted with            one or more substituents selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, (1-2C)alkyl, 4-7-membered            heterocyclyl, NR_(c)R_(d), OR_(c), C(O)R_(c), C(O)OR_(c),            OC(O)R_(c), N(R_(d))OR_(c), C(O)N(R_(d))R_(c),            N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is 0, 1 or 2),            SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c) and            R_(d) are each independently selected from H or (1-2C)alkyl;            or        -   wherein the 5- or 6-membered heteroaryl is optionally fused            to a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the            fused ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(k)R_(l),            OR_(k), C(O)R_(k), C(O)OR_(k), OC(O)R_(k), N(R_(l))OR_(k),            C(O)N(R_(l))R_(k), N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p            is 0, 1 or 2), SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l),            wherein R_(k) and R_(l) are each independently selected from            H or (1-2C)alkyl,        -   and wherein any alkyl moiety present in the substituent            group is optionally further substituted with one or more            substituents selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-2C)alkyl, NR_(m)R_(n), OR_(m), C(O)R_(m),            C(O)OR_(m), OC(O)R_(m), N(R_(n))OR_(m), C(O)N(R_(n))R_(m),            N(R_(n))C(O)R_(m), S(O)_(q)R_(m) (where q is 0, 1 or 2),            SO₂N(R_(n))R_(m), or N(R_(n))SO₂R_(m), wherein R_(m) and            R_(n) are each independently selected from H or (1-2C)alkyl;    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-4C)alkyl which is optionally substituted by halo or            (1-2C)alkoxy;        -   or R_(e) and R_(f) are linked such that, together with the            nitrogen atom to which they are attached, they form a 4-, 5-            or 6-membered heterocyclic ring, wherein said ring is            optionally substituted with one or more substituents            independently selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-2C)alkyl, NR_(g)R_(h), OR_(g), C(O)R_(g),            C(O)OR_(g), OC(O)R_(g), N(R_(h))OR_(g), C(O)N(R_(h))R_(g),            N(R_(h))C(O)R_(g), S(O)_(p)R_(h) (where p is 0, 1 or 2),            SO₂N(R_(h))R_(g), or N(R_(h))SO₂R_(g), wherein R_(g) and            R_(h) are each independently selected from H or (1-2C)alkyl;            (2) R₁ is selected from:    -   (i) a 5- or 6-membered heteroaryl optionally substituted with        one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),        -   wherein R_(a) and R_(b) are each independently selected from            H or (1-2C)alkyl;        -   and wherein any alkyl moiety present in the substituent            group is optionally further substituted with one or more            substituents selected from halo, cyano, NR_(c)R_(d), OR_(c),            or S(O)_(q)R_(c) (where q is 0, 1 or 2), wherein R_(c) and            R_(d) are each independently selected from H or (1-2C)alkyl;        -   or        -   wherein the 5- or 6-membered heteroaryl is optionally fused            to a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the            fused ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(k)R_(l),            OR_(k), C(O)R_(k), C(O)OR_(k), OC(O)R_(k), N(R_(l))OR_(k),            C(O)N(R_(l))R_(k), N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p            is 0, 1 or 2), SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l),            wherein R_(k) and R_(l) are each independently selected from            H or (1-2C)alkyl;    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-4C)alkyl which is optionally substituted by halo or            (1-2C)alkoxy;        -   or R_(e) and R_(f) are linked such that, together with the            nitrogen atom to which they are attached, they form a 4-, 5-            or 6-membered heterocyclic ring, wherein said ring is            optionally substituted with one or more substituents            independently selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-2C)alkyl, NR_(g)R_(h), OR_(g), C(O)R_(g),            C(O)OR_(g), OC(O)R_(g), N(R_(h))OR_(g), C(O)N(R_(h))R_(g),            N(R_(h))C(O)R_(g), S(O)_(p)R_(h) (where p is 0, 1 or 2),            SO₂N(R_(h))R_(g), or N(R_(h))SO₂R_(g), wherein R_(g) and            R_(h) are each independently selected from H or (1-2C)alkyl;            (3) R₁ is selected from:    -   (i) a 5- or 6-membered heteroaryl optionally substituted with        one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), or S(O)_(p)R_(a) (where p is 0, 1 or 2), wherein        R_(a) and R_(b) are each independently selected from H or        (1-2C)alky, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from OR_(c),        -   wherein R_(c) and R_(d) are each independently selected from            H or (1-2C)alkyl; or        -   wherein the 5- or 6-membered heteroaryl is optionally fused            to a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the            fused ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(k)R_(l),            OR_(k), C(O)R_(k), or S(O)_(p)R_(k) (where p is 0, 1 or 2),            wherein R_(k) and R_(l) are each independently selected from            H or (1-2C)alkyl;    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h),            OR_(g), C(O)R_(g), or S(O)_(p)R_(h) (where p is 0, 1 or 2),            wherein R_(g) and R_(h) are each independently selected from            H or (1-2C)alkyl;            (4) R₁ is selected from:    -   (i) a 5- or 6-membered heteroaryl optionally substituted with        one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, (1-2C)alkyl, NR_(a)R_(b), or OR_(a),        wherein R_(a) and R_(b) are each independently selected from H        or (1-2C)alkyl, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from OR_(c), wherein R_(c) and R_(d)        are each independently selected from H or (1-2C)alkyl; or        -   wherein the 5- or 6-membered heteroaryl is optionally fused            to a 4-, 5-, or 6-membered heterocyclic ring, wherein the            fused ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, (1-2C)alkyl, NR_(k)R_(l), or OR_(k),            wherein R_(k) and R_(l) are each independently selected from            H or (1-2C)alkyl;    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (5) R₁ is selected from:    -   (i) a 5- or 6-membered heteroaryl comprising 1, 2, 3 or 4        nitrogen atoms or 1 or 2 nitrogen atoms and one oxygen atom,        said heteroaryl being optionally substituted with one or more        substituents independently selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,        (1-2C)alkyl, NR_(a)R_(b), or OR_(a), wherein R_(a) and R_(b) are        each independently selected from H or (1-2C)alkyl, and wherein        any alkyl moiety present in the substituent group is optionally        further substituted with one or more substituents selected from        OR_(c), wherein R_(c) and R_(d) are each independently selected        from H or (1-2C)alkyl; or        -   wherein the 5- or 6-membered heteroaryl is optionally fused            to a 4-, 5-, or 6-membered heterocyclic ring, wherein the            fused ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, (1-2C)alkyl, NR_(k)R_(l), or OR_(k),            wherein R_(k) and R_(l) are each independently selected from            H or (1-2C)alkyl;    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring            comprising one or two further heteroatoms selected from N, O            or S, wherein said ring is optionally substituted with one            or more substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (6) R₁ is selected from:    -   (i) a 5-membered heteroaryl optionally substituted with one or        more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, (1-2C)alkyl, NR_(a)R_(b), or OR_(a),        wherein R_(a) and R_(b) are each independently selected from H        or (1-2C)alkyl, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from OR_(c), wherein R_(c) and R_(d)        are each independently selected from H or (1-2C)alkyl; or        -   wherein the 5-membered heteroaryl is optionally fused to a            4-, 5-, or 6-membered heterocyclic ring, wherein the fused            ring system is optionally substituted by one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, (1-2C)alkyl, NR_(k)R_(l), or OR_(k),            wherein R_(k) and R_(l) are each independently selected from            H or (1-2C)alkyl;    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (7) R₁ is selected from:    -   (i) a heteroaryl of the formula:

-   -   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected            from hydrogen halo, trifluoromethyl, difluoromethyl,            trifluoromethoxy, difluoromethoxy, cyano, nitro,            (1-2C)alkyl, NR_(a)R_(b), OR_(a), wherein R_(a) and R_(b)            are each independently selected from H or (1-2C)alkyl, and            wherein any alkyl moiety present in the substituent group is            optionally further substituted with one or more substituents            selected from halo, cyano, NR_(c)R_(d), OR_(c), wherein            R_(c) and R_(d) are each independently selected from H or            (1-2C)alkyl; and one of X₁, X₂ and X₃ is O or NR₁₃, wherein            R₁₃ is hydrogen or a (1-2C)alkyl group which is optionally            substituted by one or more substituents selected from halo,            hydroxy and (1-2C)alkoxy;

    -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen or a        (1-2C)alkyl group which is optionally substituted by one or more        substituents selected from halo, hydroxy and (1-2C)alkoxy; or

    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (8) R₁ is selected from:

    -   (i) a heteroaryl of the formula:

-   -   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected            from hydrogen, cyano or a (1-2C)alkyl group which is            optionally substituted by one or more substituents selected            from hydroxy and (1-2C)alkoxy;        -   and one of X₁, X₂ and X₃ is O or NR₁₃, wherein R₁₃ is            hydrogen or a (1-2C)alkyl group;        -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen            or a (1-2C)alkyl group; or

    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (9) R_(i) is selected from:

    -   (i) a heteroaryl of the formula:

-   -   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected            from hydrogen, cyano or a (1-2C)alkyl group which is            optionally substituted by one or more substituents selected            from hydroxy and (1-2C)alkoxy;        -   and one of X₁, X₂ and X₃ is O or NR₁₃, wherein R₁₃ is            hydrogen or a (1-2C)alkyl group;        -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen            or a (1-2C)alkyl group; or

    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (10) R₁ is selected from:

    -   (i) a 5-membered heteroaryl of the formula:

-   -   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected            from hydrogen or a (1-2C)alkyl group which is optionally            substituted by one or more substituents selected from            hydroxy and (1-2C)alkoxy; or

    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl; or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring, wherein            said ring is optionally substituted with one or more            substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(g)R_(h), or            OR_(g), wherein R_(g) and R_(h) are each independently            selected from H or (1-2C)alkyl;            (11) R₁ is selected from:

    -   (i) a 5-membered heteroaryl of the formula:

-   -   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected            from hydrogen or a (1-2C)alkyl group which is optionally            substituted by one or more substituents selected from            hydroxy and (1-2C)alkoxy; or

    -   (ii) a group —C(O)N(R_(f))R_(e)— or —S(O)₂N(R_(f))R_(e)—;        -   wherein R_(e) and R_(f) are each independently selected from            H or (1-2C)alkyl, or R_(e) and R_(f) are linked such that,            together with the nitrogen atom to which they are attached,            they form a 4-, 5- or 6-membered heterocyclic ring;            (12) R₁ is a 5- or 6-membered heteroaryl optionally            substituted with one or more substituents independently            selected from halo, trifluoromethyl, difluoromethyl,            trifluoromethoxy, difluoromethoxy, cyano, nitro,            (1-2C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a),            OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a),            N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1 or 2),            SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),

wherein R_(a) and R_(b) are each independently selected from H or(1-2C)alkyl, and wherein any alkyl moiety present in the substituentgroup is optionally further substituted with one or more substituentsselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, (1-2C)alkyl, 4-7-membered heterocyclyl,NR_(c)R_(d), OR_(c), C(O)R_(c), C(O)OR_(c), OC(O)R_(c), N(R_(d))OR_(c),C(O)N(R_(d))R_(c), N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is 0, 1 or2), SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c) and R_(d) areeach independently selected from H or (1-2C)alkyl;

or wherein the 5- or 6-membered heteroaryl is optionally fused to 4-,5-, 6- or 7-membered heterocyclic ring, wherein the fused ring system isoptionally substituted by one or more substituents independentlyselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(k)R_(l), OR_(k),C(O)R_(k), C(O)OR_(k), OC(O)R_(k), N(R_(l))OR_(k), C(O)N(R_(l))R_(k),N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p is 0, 1 or 2),SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l); wherein R_(k) and R_(l) are eachindependently selected from H or (1-2C)alkyl;

and wherein any alkyl moiety present in the substituent group isoptionally further substituted with one or more substituents selectedfrom halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(m)R_(n), OR_(m),C(O)R_(m), C(O)OR_(m), OC(O)R_(m), N(R_(n))OR_(m), C(O)N(R_(n))R_(m),N(R_(n))C(O)R_(m), S(O)_(q)R_(m) (where q is 0, 1 or 2),SO₂N(R_(n))R_(m), or N(R_(n))SO₂R_(m), wherein R_(m) and R_(n) are eachindependently selected from H or (1-2C)alkyl;

(13) R_(i) is a 5- or 6-membered heteroaryl optionally substituted withone or more substituents independently selected from halo,trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy,cyano, nitro, (1-2C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a),OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a),S(O)_(p)R_(a) (where p is 0, 1 or 2), SO₂N(R_(b))R_(a), orN(R_(b))SO₂R_(a),

wherein R_(a) and R_(b) are each independently selected from H or(1-2C)alkyl;

and wherein any alkyl moiety present in the substituent group isoptionally further substituted with one or more substituents selectedfrom halo, cyano, NR_(c)R_(d), OR_(c), or S(O)_(q)R_(c) (where q is 0, 1or 2), wherein R_(c) and R_(d) are each independently selected from H or(1-2C)alkyl; or

wherein the 5- or 6-membered heteroaryl is optionally fused to 4-, 5-,6- or 7-membered heterocyclic ring, wherein the fused ring system isoptionally substituted by one or more substituents independentlyselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(k)R_(l), OR_(k),C(O)R_(k), C(O)OR_(k), OC(O)R_(k), N(R_(l))OR_(k), C(O)N(R_(l))R_(k),N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p is 0, 1 or 2),SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l); wherein R_(k) and R_(l) are eachindependently selected from H or (1-2C)alkyl;

(14) R₁ is a 5- or 6-membered heteroaryl optionally substituted with oneor more substituents independently selected from halo, trifluoromethyl,difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,(1-2C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), or S(O)_(p)R_(a) (where pis 0, 1 or 2), wherein R_(a) and R_(b) are each independently selectedfrom H or (1-2C)alky, and wherein any alkyl moiety present in thesubstituent group is optionally further substituted with one or moresubstituents selected from OR_(c), wherein R_(c) and R_(d) are eachindependently selected from H or (1-2C)alkyl; or

wherein the 5- or 6-membered heteroaryl is optionally fused to 4-, 5-,6- or 7-membered heterocyclic ring, wherein the fused ring system isoptionally substituted by one or more substituents independentlyselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, nitro, (1-2C)alkyl, NR_(k)R_(l), OR_(k),C(O)R_(k), or S(O)_(p)R_(k) (where p is 0, 1 or 2), wherein R_(k) andR_(l) are each independently selected from H or (1-2C)alkyl;

(15) R₁ is a 5- or 6-membered heteroaryl optionally substituted with oneor more substituents independently selected from halo, trifluoromethyl,difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, (1-2C)alkyl,NR_(a)R_(b), or OR_(a), wherein R_(a) and R_(b) are each independentlyselected from H or (1-2C)alkyl, and wherein any alkyl moiety present inthe substituent group is optionally further substituted with one or moresubstituents selected from OR_(c), wherein R_(c) and R_(d) are eachindependently selected from H or (1-2C)alkyl; or

wherein the 5- or 6-membered heteroaryl is optionally fused to 4-, 5-,or 6-membered heterocyclic ring, wherein the fused ring system isoptionally substituted by one or more substituents independentlyselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, (1-2C)alkyl, NR_(k)R_(l), or OR_(k), whereinR_(k) and R_(l) are each independently selected from H or (1-2C)alkyl;

(16) R₁ is a 5- or 6-membered heteroaryl comprising 1, 2, 3 or 4nitrogen atoms or 1 or 2 nitrogen atoms and one oxygen atom, saidheteroaryl being optionally substituted with one or more substituentsindependently selected from halo, trifluoromethyl, difluoromethyl,trifluoromethoxy, difluoromethoxy, cyano, (1-2C)alkyl, NR_(a)R_(b), orOR_(a), wherein R_(a) and R_(b) are each independently selected from Hor (1-2C)alkyl, and wherein any alkyl moiety present in the substituentgroup is optionally further substituted with one or more substituentsselected from OR_(c), wherein R_(c) and R_(d) are each independentlyselected from H or (1-2C)alkyl; or

wherein the 5- or 6-membered heteroaryl is optionally fused to 4-, 5-,or 6-membered heterocyclic ring, wherein the fused ring system isoptionally substituted by one or more substituents independentlyselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, (1-2C)alkyl, NR_(k)R_(l), or OR_(k), whereinR_(k) and R_(l) are each independently selected from H or (1-2C)alkyl;

(17) R₁ is a 5-membered heteroaryl optionally substituted with one ormore substituents independently selected from halo, trifluoromethyl,difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, (1-2C)alkyl,NR_(a)R_(b), or OR_(a), wherein R_(a) and R_(b) are each independentlyselected from H or (1-2C)alkyl, and wherein any alkyl moiety present inthe substituent group is optionally further substituted with one or moresubstituents selected from OR_(c), wherein R_(c) and R_(d) are eachindependently selected from H or (1-2C)alkyl; or

wherein the 5-membered heteroaryl is optionally fused to 4-, 5-, or6-membered heterocyclic ring, wherein the fused ring system isoptionally substituted by one or more substituents independentlyselected from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyano, (1-2C)alkyl, NR_(k)R_(l), or OR_(k), whereinR_(k) and R_(l) are each independently selected from H or (1-2C)alkyl;

(18) R₁ is a heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen halo, trifluoromethyl, difluoromethyl,        trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-2C)alkyl,        NR_(a)R_(b), OR_(a), wherein R_(a) and R_(b) are each        independently selected from H or (1-2C)alkyl, and wherein any        alkyl moiety present in the substituent group is optionally        further substituted with one or more substituents selected from        halo, cyano, NR_(c)R_(d), OR_(c), wherein R_(c) and R_(d) are        each independently selected from H or (1-2C)alkyl; and one of        X₁, X₂ and X₃ is O or NR₁₃, wherein R₁₃ is hydrogen or a        (1-2C)alkyl group which is optionally substituted by one or more        substituents selected from halo, hydroxy and (1-2C)alkoxy;    -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen or a        (1-2C)alkyl group which is optionally substituted by one or more        substituents selected from halo, hydroxy and (1-2C)alkoxy;        (19) R₁ is a heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen cyano or a (1-2C)alkyl group which is optionally        substituted by one or more substituents selected from hydroxy        and (1-2C)alkoxy;    -   and one of X₁, X₂ and X₃ is O or NR₁₃, wherein R₁₃ is hydrogen        or a (1-2C)alkyl group;    -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen or a        (1-2C)alkyl group;        (20) R_(i) is a heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen, cyano or a (1-2C)alkyl group which is optionally        substituted by one or more substituents selected from hydroxy        and (1-2C)alkoxy;    -   and one of X₁, X₂ and X₃ is O or NR₁₃, wherein R₁₃ is hydrogen        or a (1-2C)alkyl group;    -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen or a        (1-2C)alkyl group;        (21) R₁ is a heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen or a (1-2C)alkyl group which is optionally substituted        by one or more substituents selected from hydroxy and        (1-2C)alkoxy;    -   and one of X₁, X₂ and X₃ is O or NR₁₃, wherein R₁₃ is hydrogen        or a (1-2C)alkyl group;    -   and one of X₄ and X₅ is O or NR₁₄, wherein R₁₄ is hydrogen or a        (1-2C)alkyl group;        (22) R_(i) is a heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen or a (1-2C)alkyl group which is optionally substituted        by one or more substituents selected from hydroxy and        (1-2C)alkoxy;        (23) R_(i) is a 5-membered heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen or a (1-2C)alkyl group which is optionally substituted        by one or more substituents selected from hydroxy and        (1-2C)alkoxy;        (24) R_(i) is a 5-membered heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen or a (1-2C)alkyl group which is optionally substituted        by one or more substituents selected from hydroxy and        (1-2C)alkoxy;        (25) R_(i) is a 5-membered heteroaryl of the formula:

-   -   wherein R₁₀, R₁₁ and R₁₂ are each independently selected from        hydrogen or a (1-2C)alkyl group;        (26) R₁ is a 5-membered heteroaryl of the formula:

-   -   wherein R₁₀ and R₁₁ are each independently selected from        hydrogen or a (1-2C)alkyl group which is optionally substituted        by one or more substituents selected from hydroxy and        (1-2C)alkoxy;        (27) R₁ is a 5-membered heteroaryl of the formula:

-   -   wherein R₁₀ and R₁₁ are each independently selected from        hydrogen or a (1-2C)alkyl group;        (28) R_(i) is a 5- or 6-membered heteroaryl of the formula:

-   -   wherein R₁₀ is methyl and R₁₁ is hydrogen or methyl;        (29) R_(i) is a 5-membered heteroaryl of the formula:

(30) R_(i) is a triazole or imidazole ring optionally substituted withone or more substituents independently selected from halo,trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy,cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a),OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a),S(O)_(p)R_(a) (where p is 0, 1 or 2), SO₂N(R_(b))R_(a), orN(R_(b))SO₂R_(a),

-   -   wherein R_(a) and R_(b) are each independently selected from H        or (1-4C)alkyl, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,        (1-4C)alkyl, 4-7-membered heterocyclyl, NR_(c)R_(d), OR_(c),        C(O)R_(c), C(O)OR_(c), OC(O)R_(c), N(R_(d))OR_(c),        C(O)N(R_(d))R_(c), N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is        0, 1 or 2), SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c)        and R_(d) are each independently selected from H or (1-4C)alkyl;    -   wherein the triazole or imidazole ring is optionally fused to a        4-, 5-, 6- or 7-membered heterocyclic ring, wherein the fused        ring system is optionally substituted by one or more        substituents independently selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,        (1-4C)alkyl, NR_(k)R_(l), OR_(k), C(O)R_(k), C(O)OR_(k),        OC(O)R_(k), N(R_(l))OR_(k), C(O)N(R_(l))R_(k),        N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p is 0, 1 or 2),        SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l), wherein R_(k) and R_(l)        are each independently selected from H or (1-4C)alkyl,    -   and wherein any alkyl moiety present in the substituent group is        optionally further substituted with one or more substituents        selected from halo, trifluoromethyl, difluoromethyl,        trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C)alkyl,        4-7-membered heterocyclyl, NR_(m)R_(n), OR_(m), C(O)R_(m),        C(O)OR_(m), OC(O)R_(m), N(R_(n))OR_(m), C(O)N(R_(n))R_(m),        N(R_(n))C(O)R_(m), S(O)_(q)R_(m) (where q is 0, 1 or 2),        SO₂N(R_(n))R_(m), or N(R_(n))SO₂R_(m), wherein R_(m) and R_(n)        are each independently selected from H or (1-4C)alkyl;        (31) R₁ is a triazole or imidazole ring optionally substituted        with one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),    -   wherein R_(a) and R_(b) are each independently selected from H        or (1-4C)alkyl, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,        (1-4C)alkyl, 4-7-membered heterocyclyl, NR_(c)R_(d), OR_(c),        C(O)R_(c), C(O)OR_(c), OC(O)R_(c), N(R_(d))OR_(c),        C(O)N(R_(d))R_(c), N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is        0, 1 or 2), SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c)        and R_(d) are each independently selected from H or (1-4C)alkyl;        (32) R₁ is a triazole or imidazole ring optionally substituted        with one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a)        and R_(b) are each independently selected from H or (1-4C)alkyl;        (33) R₁ is a triazole or imidazole ring optionally substituted        with one or more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, (1-4C)alkyl, NR_(a)R_(b), OR_(a), wherein R_(a)        and R_(b) are each independently selected from H or (1-2C)alkyl;        (34) R₁ is a triazole or imidazole ring optionally substituted        with (1-2C)alkyl;        (35) R₁ is a triazole ring optionally substituted with one or        more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),    -   wherein R_(a) and R_(b) are each independently selected from H        or (1-4C)alkyl, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,        (1-4C)alkyl, 4-7-membered heterocyclyl, NR_(c)R_(d), OR_(c),        C(O)R_(c), C(O)OR_(c), OC(O)R_(c), N(R_(d))OR_(c),        C(O)N(R_(d))R_(c), N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is        0, 1 or 2), SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c)        and R_(d) are each independently selected from H or (1-4C)alkyl;    -   wherein the triazole or imidazole ring is optionally fused to a        4-, 5-, 6- or 7-membered heterocyclic ring, wherein the fused        ring system is optionally substituted by one or more        substituents independently selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,        (1-4C)alkyl, NR_(k)R_(l), OR_(k), C(O)R_(k), C(O)OR_(k),        OC(O)R_(k), N(R_(l))OR_(k), C(O)N(R_(l))R_(k),        N(R_(l))C(O)R_(k), S(O)_(p)R_(k) (where p is 0, 1 or 2),        SO₂N(R_(k))R_(l), or N(R_(k))SO₂R_(l), wherein R_(k) and R_(l)        are each independently selected from H or (1-4C)alkyl,    -   and wherein any alkyl moiety present in the substituent group is        optionally further substituted with one or more substituents        selected from halo, trifluoromethyl, difluoromethyl,        trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C)alkyl,        4-7-membered heterocyclyl, NR_(m)R_(n), OR_(m), C(O)R_(m),        C(O)OR_(m), OC(O)R_(m), N(R_(n))OR_(m), C(O)N(R_(n))R_(m),        N(R_(n))C(O)R_(m), S(O)_(q)R_(m) (where q is 0, 1 or 2),        SO₂N(R_(n))R_(m), or N(R_(n))SO₂R_(m), wherein R_(m) and R_(n)        are each independently selected from H or (1-4C)alkyl;        (36) R₁ is a triazole ring optionally substituted with one or        more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),    -   wherein R_(a) and R_(b) are each independently selected from H        or (1-4C)alkyl, and wherein any alkyl moiety present in the        substituent group is optionally further substituted with one or        more substituents selected from halo, trifluoromethyl,        difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro,        (1-4C)alkyl, 4-7-membered heterocyclyl, NR_(c)R_(d), OR_(c),        C(O)R_(c), C(O)OR_(c), OC(O)R_(c), N(R_(d))OR_(c),        C(O)N(R_(d))R_(c), N(R_(d))C(O)R_(c), S(O)_(q)R_(c) (where q is        0, 1 or 2), SO₂N(R_(d))R_(c), or N(R_(d))SO₂R_(c), wherein R_(c)        and R_(d) are each independently selected from H or (1-4C)alkyl;        (37) R₁ is a triazole ring optionally substituted with one or        more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(a)R_(b), OR_(a),        C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),        C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is        0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a)        and R_(b) are each independently selected from H or (1-4C)alkyl;        (38) R₁ is a triazole ring optionally substituted with one or        more substituents independently selected from halo,        trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, (1-4C)alkyl, NR_(a)R_(b), OR_(a), wherein R_(a)        and R_(b) are each independently selected from H or (1-2C)alkyl;        (39) R₁ is a triazole ring optionally substituted with        (1-2C)alkyl;        (40) R₂ is selected from chloro, (1-2C)alkoxy or        (1-2C)fluoroalkoxy;        (41) R₂ is selected from chloro, methoxy, ethoxy,        difluoromethoxy or trifluoromethoxy;        (42) R₂ is selected from methoxy, ethoxy, or difluoromethoxy;        (43) R₂ is methoxy;        (44) R₂ is ethoxy;        (45) R₂ is difluoromethoxy;        (46) either:    -   (i) R₃ is selected from hydrogen or (1-2C)alkyl and R₄ is        selected from (1-6C)alkyl, (3-9C)cycloalkyl,        (3-9C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl,        heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl,        heteroaryl-(1-2C)alkyl, and        -   wherein R₄ is optionally further substituted by one or more            substituents selected from hydroxy, fluoro, chloro, cyano,            CF₃, CHF₂, OCF₃, OCHF₂, (1-4C)alkyl, NR_(o)R_(p), OR_(o),            C(O)R_(o), C(O)OR_(p), OC(O)R_(o), N(R_(p))OR_(o),            C(O)N(R_(p))R_(o), N(R_(p))C(O)R_(o), S(O)_(p)R_(o) (where p            is 0, 1 or 2), SO₂N(R_(p))R_(o), or N(R_(p))SO₂R_(o) or            (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, wherein            R_(o) and R_(p) are each independently selected from H or            (1-4C)alkyl, (3-6C)cycloalkyl or            (3-6C)cycloalkyl-(1-2C)alkyl; or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-6- or 7-membered heterocyclic ring,        -   wherein said ring is optionally fused to a further 3-, 4-,            5- or 6-membered ring carbocyclic or heterocyclic ring, a 5-            or 6-membered heteroaryl ring or a phenyl ring to form a            bi-cyclic heterocyclic system, or        -   linked through a spiro carbon atom to a further 4-, 5- or            6-membered ring carbocyclic or heterocyclic ring to form a            spiro bicyclic ring system;        -   and wherein the heterocyclic ring, bicyclic ring system or            spiro bicyclic ring system is optionally substituted by one            or more substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j),            OR_(i), C(O)R_(i), C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i),            C(O)N(R_(j))R_(i), N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q            is 0, 1 or 2), SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i),            wherein R_(i) and R_(j) are each independently selected from            H or (1-4C)alkyl;            (47) either:    -   (i) R₃ is selected from hydrogen or methyl and R₄ is selected        from (1-6C)alkyl, (3-6C)cycloalkyl,        (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or 6-membered heterocyclyl,        a 4, 5 or 6-membered heterocyclyl-(1-2C)alkyl, and wherein R₄ is        optionally further substituted by one or more substituents        selected from hydroxy, fluoro, chloro, cyano, CF₃, CHF₂, OCF₃,        OCHF₂, (1-4C)alkyl, NR_(o)R_(p), OR_(o), C(O)R_(o), C(O)OR_(p),        OC(O)R_(o), N(R_(p))OR_(o), C(O)N(R_(p))R_(o),        N(R_(p))C(O)R_(o), S(O)_(p)R_(o) (where p is 0, 1 or 2),        SO₂N(R_(p))R_(o), N(R_(p))SO₂R_(o) or (3-6C)cycloalkyl, wherein        R_(o) and R_(p) are each independently selected from H or        (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl-(1-2C)alkyl;        or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-6- or 7-membered heterocyclic ring,        -   wherein said ring is optionally fused to a further 3-, 4-,            5- or 6-membered ring carbocyclic or heterocyclic ring to            form a bi-cyclic heterocyclic system, or        -   linked through a spiro carbon atom to a further 4-, 5- or            6-membered ring carbocyclic or heterocyclic ring to form a            spiro bicyclic ring system;        -   and wherein the heterocyclic ring, bicyclic ring system or            spiro bicyclic ring system is optionally substituted by one            or more substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j),            OR_(i), C(O)R_(i), C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i),            C(O)N(R_(j))R_(i), N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q            is 0, 1 or 2), SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i),            wherein R_(i) and R_(j) are each independently selected from            H or (1-4C)alkyl;            (48) either:    -   (i) R₃ is selected from hydrogen or methyl and R₄ is selected        from (1-6C)alkyl, (3-6C)cycloalkyl,        (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or 6-membered heterocyclyl,        a 4, 5 or 6-membered heterocyclyl-(1-2C)alkyl, and wherein R₄ is        optionally further substituted by one or more substituents        selected from hydroxy, fluoro, chloro, cyano, CF₃, CHF₂, OCF₃,        OCHF₂, (1-4C)alkyl, NR_(o)R_(p), OR_(o), S(O)_(p)R_(o) (where p        is 0, 1 or 2), or (3-6C)cycloalkyl, wherein R_(o) and R_(p) are        each independently selected from H or (1-4C)alkyl,        (3-6C)cycloalkyl or (3-6C)cycloalkyl-(1-2C)alkyl; or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-6- or 7-membered heterocyclic ring,        -   wherein said ring is optionally fused to a further 3-, 4-,            5- or 6-membered ring carbocyclic or heterocyclic ring to            form a bi-cyclic heterocyclic system, or linked through a            spiro carbon atom to a further 4-, 5- or 6-membered ring            carbocyclic or heterocyclic ring to form a spiro bicyclic            ring system;        -   and wherein the heterocyclic ring, bicyclic ring system or            spiro bicyclic ring system is optionally substituted by one            or more substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j),            OR_(i), C(O)R_(i), S(O)_(q)R_(i) (where q is 0, 1 or 2),            wherein R_(i) and R_(j) are each independently selected from            H or (1-4C)alkyl;            (49) either:    -   (i) R₃ is selected from hydrogen and R₄ is selected from        (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, a        4, 5 or 6-membered heterocyclyl, a 4, 5 or 6-membered        heterocyclyl-(1-2C)alkyl, and wherein R₄ is optionally further        substituted by one or more substituents selected from hydroxy,        fluoro, chloro, cyano, CF₃, CHF₂, OCF₃, OCHF₂, (1-4C)alkyl,        NR_(o)R_(p), OR_(o), S(O)_(p)R_(o) (where p is 0, 1 or 2), or        (3-6C)cycloalkyl, wherein R_(o) and R_(p) are each independently        selected from H or (1-4C)alkyl, (3-6C)cycloalkyl or        (3-6C)cycloalkyl-(1-2C)alkyl; or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-, or 6-membered heterocyclic ring,        -   wherein said ring is optionally linked through a spiro            carbon atom to a further 4-, 5- or 6-membered ring            carbocyclic or heterocyclic ring to form a spiro bicyclic            ring system;        -   and wherein the heterocyclic ring, bicyclic ring system or            spiro bicyclic ring system is optionally substituted by one            or more substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j),            OR_(i), C(O)R_(i), S(O)_(q)R_(i) (where q is 0, 1 or 2),            wherein R_(i) and R_(j) are each independently selected from            H or (1-4C)alkyl;            (50) either:    -   (i) R₃ is selected from hydrogen and R₄ is selected from        (1-6C)alkyl, (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or 6-membered        heterocyclyl, a 4, 5 or 6-membered heterocyclyl-(1-2C)alkyl, and        wherein R₄ is optionally further substituted by one or more        substituents selected from hydroxy, fluoro, chloro, cyano, CF₃,        CHF₂, OCF₃, OCHF₂, (1-4C)alkyl, NR_(o)R_(p) or OR_(o), wherein        R_(o) and R_(p) are each independently selected from H or        (1-4C)alkyl; or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-, or 6-membered heterocyclic ring,        -   wherein said ring is optionally linked through a spiro            carbon atom to a further 4-, 5- or 6-membered ring            carbocyclic or heterocyclic ring to form a spiro bicyclic            ring system;        -   and wherein the heterocyclic ring, bicyclic ring system or            spiro bicyclic ring system is optionally substituted by one            or more substituents independently selected from halo,            trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j),            OR_(i), C(O)R_(i), S(O)_(q)R_(i) (where q is 0, 1 or 2),            wherein R_(i) and R_(j) are each independently selected from            H or (1-4C)alkyl;            (51) either:    -   (i) R₃ is selected from hydrogen and R₄ is selected from        (1-6C)alkyl, (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or 6-membered        heterocyclyl, a 4, 5 or 6-membered heterocyclyl-(1-2C)alkyl, and        wherein R₄ is optionally further substituted by one or more        substituents selected from hydroxyl, (1-4C)alkyl or OR_(o),        wherein R_(o) is selected from H or (1-2C)alkyl; or    -   (ii) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-, or 6-membered heterocyclic ring,        -   wherein said ring is optionally linked through a spiro            carbon atom to a further 4-, 5- or 6-membered ring            carbocyclic or heterocyclic ring to form a spiro bicyclic            ring system;        -   and wherein the heterocyclic ring, bicyclic ring system or            spiro bicyclic ring system is optionally substituted by one            or more substituents independently selected from halo,            trifluoromethyl, cyano, (1-4C)alkyl, NR_(i)R_(j), OR_(i),            wherein R_(i) and R_(j) are each independently selected from            H or (1-2C)alkyl;            (52) R₃ is selected from hydrogen or (1-3C)alkyl and R₄ is            selected from (1-6C)alkyl, (3-9C)cycloalkyl,            (3-9C)cycloalkyl-(1-4C)alkyl, aryl, aryl-(1-4C)alkyl,            heterocyclyl, heterocyclyl-(1-4C)alkyl, heteroaryl,            heteroaryl-(1-4C)alkyl, and wherein R₄ is optionally further            substituted by one or more substituents selected from            hydroxy, fluoro, chloro, cyano, CF₃, CHF₂, OCF₃, OCHF₂,            (1-4C)alkyl, NR_(o)R_(p), OR_(o), C(O)R_(o), C(O)OR_(p),            OC(O)R_(o), N(R_(p))OR_(o), C(O)N(R_(p))R_(o),            N(R_(p))C(O)R_(o), S(O)_(p)R_(o) (where p is 0, 1 or 2),            SO₂N(R_(p))R_(o), or N(R_(p))SO₂R_(o) or (3-6C)cycloalkyl,            (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or 6-membered            heterocyclyl, a 4, 5 or 6-membered heterocyclyl-(1-2C)alkyl,            wherein R_(o) and R_(p) are each independently selected from            H or (1-4C)alkyl, (3-6C)cycloalkyl or            (3-6C)cycloalkyl-(1-4C)alkyl;            (53) R₃ is selected from hydrogen and R₄ is selected from            (1-6C)alkyl, (3-6C)cycloalkyl-(1-2C)alkyl, a 4, 5 or            6-membered heterocyclyl, a 4, 5 or 6-membered            heterocyclyl-(1-2C)alkyl, and wherein R₄ is optionally            further substituted by one or more substituents selected            from hydroxyl, (1-4C)alkyl or OR_(o), wherein R_(o) is            selected from H or (1-2C)alkyl            (54) R₃ and R₄ are linked such that, together with the            nitrogen atom to which they are attached, they form a            nitrogen-linked 4-, 5-6- or 7-membered heterocyclic ring;            and wherein the heterocyclic ring is optionally substituted            by one or more substituents independently selected from            halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,            difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j),            OR_(i), C(O)R_(i), C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i),            C(O)N(R_(j))R_(i), N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q            is 0, 1 or 2), SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i),            wherein R_(i) and R_(j) are each independently selected from            H or (1-4C)alkyl;            (55) R₃ and R₄ are linked such that, together with the            nitrogen atom to which they are attached, they form a            nitrogen-linked 4-, 5-6- or 7-membered heterocyclic ring,            wherein said ring is fused to a further 3-, 4-, 5- or            6-membered ring carbocyclic or heterocyclic ring, a 5- or            6-membered heteroaryl ring or a phenyl ring to form a            bi-cyclic heterocyclic system; and wherein the bicyclic ring            system is optionally substituted by one or more substituents            independently selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-4C)alkyl, NR_(i)R_(j), OR_(i), C(O)R_(i),            C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i), C(O)N(R_(j))R_(i),            N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q is 0, 1 or 2),            SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i), wherein R_(i) and            R_(j) are each independently selected from H or (1-4C)alkyl;            (56) R₃ and R₄ are linked such that, together with the            nitrogen atom to which they are attached, they form a            nitrogen-linked 4-, 5-6- or 7-membered heterocyclic ring            wherein said ring is fused to a further 3-, 4-, 5- or            6-membered ring carbocyclic or heterocyclic ring, a 5- or            6-membered heteroaryl ring or a phenyl ring to form a            bi-cyclic heterocyclic system; and wherein the bicyclic ring            system is optionally substituted by one or more substituents            independently selected from halo, trifluoromethyl,            difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano,            nitro, (1-4C)alkyl, NR_(i)R_(j), OR_(i), C(O)R_(i),            C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i), C(O)N(R_(j))R_(i),            N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q is 0, 1 or 2),            SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i), wherein R_(i) and            R_(j) are each independently selected from H or (1-4C)alkyl            (57) R₃ and R₄ are linked such that, together with the            nitrogen atom to which they are attached, they form a            nitrogen-linked 4-, 5-6- or 7-membered heterocyclic ring            wherein said ring is linked through a spiro carbon atom to a            further 4-, 5- or 6-membered ring carbocyclic or            heterocyclic ring to form a spiro bicyclic ring system;    -   and wherein the spiro bicyclic ring system is optionally        substituted by one or more substituents independently selected        from halo, trifluoromethyl, difluoromethyl, trifluoromethoxy,        difluoromethoxy, cyano, nitro, (1-4C)alkyl, NR_(i)R_(j), OR_(i),        C(O)R_(i), C(O)OR_(i), OC(O)R_(i), N(R_(j))OR_(i),        C(O)N(R_(j))R_(i), N(R_(j))C(O)R_(i), S(O)_(q)R_(i) (where q is        0, 1 or 2), SO₂N(R_(j))R_(i), or N(R_(j))SO₂R_(i), wherein R_(i)        and R_(j) are each independently selected from H or (1-4C)alkyl;        (58) R₃ and R₄ are linked such that, together with the nitrogen        atom to which they are attached, they form a nitrogen-linked 4-,        5-6- or 7-membered heterocyclic ring wherein said ring is linked        through a spiro carbon atom to a further 4-, 5- or 6-membered        ring carbocyclic or heterocyclic ring to form a spiro bicyclic        ring system;    -   and wherein the spiro bicyclic ring system is optionally        substituted by one or more substituents independently selected        from halo, trifluoromethyl, cyano, (1-4C)alkyl, NR_(i)R_(j),        OR_(i), wherein R_(i) and R_(j) are each independently selected        from H or (1-2C)alkyl.

Suitably, R₁ is as defined in any one of paragraphs (1) to (39) above.In an embodiment, R₁ is as defined in any one of paragraphs (12) to (39)above. In a particular embodiment, R₁ is as defined in any one ofparagraphs (20) to (39) above.

Suitably, R₂ is as defined in any one of paragraphs (40) to (45) above.In an embodiment, R₂ is as defined in paragraph (42) above. In aparticular embodiment, R₁ is as defined in (44) above.

Suitably, R₃ and R₄ are as defined in any one of paragraphs (46) to (58)above. In an embodiment, R₃ and R₄ are as defined in paragraph (49)above.

In an embodiment, R₁ is a triazole or imidazole that is optionallysubstituted as defined hereinbefore.

In a particular group of compounds of the invention:

R₁ is as defined in any one of paragraphs (1) to (39) above;

R₂ is as defined in any one of paragraphs (40) to (45) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (12) to (39) above;

R₂ is as defined in paragraph (42) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (20) to (39) above;

R₂ is as defined in paragraph (42) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (22) to (39) above;

R₂ is as defined in paragraph (42) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in paragraph (25) above;

R₂ is as defined in paragraph (42) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in paragraph (26) above;

R₂ is as defined in paragraph (42) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in paragraph (27) above;

R₂ is as defined in paragraph (42) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (12) to (39) above;

R₂ is as defined in paragraph (43) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (12) to (39) above;

R₂ is as defined in paragraph (44) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (21) to (39) above;

R₂ is as defined in paragraph (43) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in any one of paragraphs (21) to (39) above;

R₂ is as defined in paragraph (44) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in paragraph (25) above;

R₂ is as defined in paragraph (43) above; and

R₃ and R₄ each have any one of the definitions set out herein.

In a further group of compounds of the invention:

R₁ is as defined in paragraph (25) above;

R₂ is as defined in paragraph (44) above; and

R₃ and R₄ each have any one of the definitions set out herein.

Particular compounds of the present invention include any one of thecompounds exemplified in the present application, or a pharmaceuticallyacceptable salt or solvate thereof, and, in particular, any one of thefollowing:

-   N2-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   1-(((2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclobutanol;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)piperidine-4-carbonitrile;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidin-3-ol;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((3-methyloxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(((2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclopropanol;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)piperidine-4-carbonitrile;-   1-(2-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-methyl-N8-neopentyl    pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-difluoroazetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-methylmorpholino)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-(dimethylamino)azetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)piperidin-4-ol;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylpyrrolidin-3-ol;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)pyrrolidine-3-carbonitrile;-   N2-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(oxazol-2-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxypyrrolidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3,3-dimethyl    azetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylpyrrolidine-3-carbonitrile;-   8-(2,2-dimethyl    azetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(3-(trifluoromethyl)azetidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-azaspiro[3.3]heptan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   (R)—N8-(3,3-dimethylbutan-2-yl)-N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   (S)—N8-(3,3-dimethyl    butan-2-yl)-N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-((1-methoxycyclobutyl)methyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(1-methylazetidin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(oxetan-3-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-ethylazetidin-3-ol;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(4-(dimethylamino)    piperidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-ethylpiperidine-4-carbonitrile;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(2-(3-methyltetrahydrofuran-3-yl)ethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(pentan-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3-ethoxy-3-methylazetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-ethyl-3-methoxyazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-ethoxy-3-ethylazetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-isopropyl-3-methoxyazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-ethoxy-3-isopropylazetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-ethylazetidine-3-carbonitrile;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-isopropylazetidine-3-carbonitrile;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,2,3-trimethylazetidine-3-carbonitrile;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxy-2,2-dimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxy-2,2,3-trimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,2-dimethylazetidine-3-carbonitrile;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(4-(dimethylamino)piperidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   4-ethyl-1-(2-((2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)piperidine-4-carbonitrile;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(2-(3-methyltetrahydrofuran-3-yl)ethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(pentan-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3-ethoxy-3-methylazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-ethyl-3-methoxyazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-ethoxy-3-ethylazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-isopropyl-3-methoxyazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-ethoxy-3-isopropylazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   3-ethyl-1-(2-((2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)azetidine-3-carbonitrile;-   3-isopropyl-1-(2-((2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)azetidine-3-carbonitrile;-   1-(2-((2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,2,3-trimethylazetidine-3-carbonitrile;-   8-(3-methoxy-2,2-dimethylazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   8-(3-methoxy-2,2,3-trimethylazetidin-1-yl)-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-2,2-dimethylazetidine-3-carbonitrile;-   8-(3,3-dimethylazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   8-(3-methoxy-3-methylazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3,3-dimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethylazetidin-1-yl)-N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethyl    azetidin-1-yl)-N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(3,3-dimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-8-(3,3-dimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-8-(3-methoxy-3-methyl    azetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethylazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   8-(3-methoxy-3-methylazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(3,3-dimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-8-(3,3-dimethylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethylazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   8-(3-methoxy-3-methylazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   8-(3,3-dimethylazetidin-1-yl)-N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethylazetidin-1-yl)-N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,4-dimethyloxazol-5-yl)-2-ethoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethylazetidin-1-yl)-N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methyl-N8-(tetra    hydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,5-dimethyloxazol-4-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,3-dimethylazetidin-1-yl)-N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-8-(4-methoxypiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methyl-8-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile;-   N2-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(2,5-dimethyloxazol-4-yl)-2-ethoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;    or a pharmaceutically acceptable salt or solvate thereof.

The various functional groups and substituents making up the compoundsof the present invention are typically chosen such that the molecularweight of the compound does not exceed 1000. More usually, the molecularweight of the compound will be less than 750, for example less than 700,or less than 650, or less than 600, or less than 550. More preferably,the molecular weight is less than 525 and, for example, is 500 or less.

Suitable or preferred features of any compounds of the present inventionmay also be suitable features of any other aspect.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the invention mayhave geometric isomeric centres (E- and Z-isomers). It is to beunderstood that the present invention encompasses all optical,diastereoisomers and geometric isomers and mixtures thereof that possessMps1 kinase inhibitory activity.

The present invention also encompasses compounds of the invention asdefined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including ¹H, ²H(D), and ³H (T);C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; and O may bein any isotopic form, including ¹⁶O and ¹⁸O; and the like.

It is also to be understood that certain compounds of the invention mayexist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms that possess Mps1 kinase inhibitory activity.

It is also to be understood that certain compounds of the invention mayexhibit polymorphism, and that the invention encompasses all such formsthat possess Mps1 kinase inhibitory activity.

Compounds of the invention may exist in a number of different tautomericforms and references to compounds of the invention include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by compounds of theinvention. Examples of tautomeric forms include keto-, enol-, andenolate-forms, as in, for example, the following tautomeric pairs:keto/enol (illustrated below), imine/enamine, amide/imino alcohol,amidine/amidine, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Compounds of the invention containing an amine function may also formN-oxides. A reference herein to a compound of the formula I thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. 1977, 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (MCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of the invention may be administered in the form of apro-drug which is broken down in the human or animal body to release acompound of the invention. A pro-drug may be used to alter the physicalproperties and/or the pharmacokinetic properties of a compound of theinvention. A pro-drug can be formed when the compound of the inventioncontains a suitable group or substituent to which a property-modifyinggroup can be attached. Examples of pro-drugs include in vivo cleavableester derivatives that may be formed at a carboxy group or a hydroxygroup in a compound of the invention and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the invention.

Accordingly, the present invention includes those compounds of theformula I as defined hereinbefore when made available by organicsynthesis and when made available within the human or animal body by wayof cleavage of a pro-drug thereof. Accordingly, the present inventionincludes those compounds of the formula I that are produced by organicsynthetic means and also such compounds that are produced in the humanor animal body by way of metabolism of a precursor compound, that is acompound of the formula I may be a synthetically-produced compound or ametabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I is one that is based on reasonable medical judgement as beingsuitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable ester thereof. An in vivo cleavable ester of a compound of theformula I containing a carboxy group is, for example, a pharmaceuticallyacceptable ester which is cleaved in the human or animal body to producethe parent acid. Suitable pharmaceutically acceptable esters for carboxyinclude C₁₋₆alkyl esters such as methyl, ethyl and tert-butyl,C₁₋₆alkoxymethyl esters such as methoxymethyl esters,C₁₋₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, C₃₋₈cycloalkylcarbonyloxy-C₁₋₆alkyl esters such ascyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters andC₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl esters such as methoxycarbonyloxymethyland 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a hydroxy group is, for example, an in vivocleavable ester or ether thereof. An in vivo cleavable ester or ether ofa compound of the formula I containing a hydroxy group is, for example,a pharmaceutically acceptable ester or ether which is cleaved in thehuman or animal body to produce the parent hydroxy compound. Suitablepharmaceutically acceptable ester forming groups for a hydroxy groupinclude inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group includeC₁₋₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups, C₁₋₁₀alkoxycarbonyl groupssuch as ethoxycarbonyl, N,N—(C₁₋₆)₂carbamoyl, 2-dialkylaminoacetyl and2-carboxyacetyl groups. Examples of ring substituents on thephenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-(C₁₋₄alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptableether forming groups for a hydroxy group include α-acyloxyalkyl groupssuch as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable amide thereof, for example an amide formed with an amine suchas ammonia, a C₁₋₄alkylamine such as methylamine, a (C₁₋₄alkyl)₂ aminesuch as dimethylamine, N-ethyl-N-methylamine or diethylamine, aC₁₋₄alkoxy-C₂₋₄alkylamine such as 2-methoxyethylamine, a phenyl-C₁₋₄alkylamine such as benzylamine and amino acids such as glycine or anester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses an amino group is, for example, an in vivocleavable amide derivative thereof. Suitable pharmaceutically acceptableamides from an amino group include, for example an amide formed withC₁₋₁₀alkanoyl groups such as an acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups. Examples of ringsubstituents on the phenylacetyl and benzoyl groups include aminomethyl,N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the formula I may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the formula I. Asstated hereinbefore, the in vivo effects of a compound of the formula Imay also be exerted by way of metabolism of a precursor compound (apro-drug).

It shall also be appreciated that compounds of formula I may also becovalently linked (at any suitable position) to other groups such as,for example, solubilising moieties (for example, PEG polymers), moietiesthat enable them to be bound to a solid support (such as, for example,biotin-containing moieties), and targeting ligands (such as antibodiesor antibody fragments).

Synthesis

In the description of the synthetic methods described below and in thereferenced synthetic methods that are used to prepare the staringmaterials, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of the experiment and workup procedures, can be selected by aperson skilled in the art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilised.

Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples.

Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

It will be appreciated that during the synthesis of the compounds of theinvention in the processes defined below, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method described in the literature or known tothe skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with the minimum disturbance of groups elsewhere inthe molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

By way of example, a suitable protecting group for an amino oralkylamino group is, for example, an acyl group, for example an alkanoylgroup such as acetyl, an alkoxycarbonyl group, for example amethoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroylgroup, for example benzoyl. The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed by, for example, hydrolysis witha suitable base such as an alkali metal hydroxide, for example lithiumor sodium hydroxide. Alternatively an acyl group such as atert-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulfuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example BF₃.OEt₂. A suitable alternative protecting groupfor a primary amino group is, for example, a phthaloyl group which maybe removed by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium, sodium hydroxide or ammonia. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

In a particular aspect, the present invention provides a method ofsynthesising a compound of the formula I, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

a) reacting a compound of formula A:

wherein R₃ and R₄ each have any one of the meanings as definedhereinbefore, and LG_(A) is a suitable leaving group;with a compound of formula B:

wherein R₁ and R₂ are as defined herein; andb) optionally thereafter, and if necessary:i) removing any protecting groups present;ii) converting the compound formula I into another compound of formulaI; and/oriii) forming a pharmaceutically acceptable salt or solvate thereof.

LG_(A) may be any suitable leaving group. Suitably LG_(A) is a halogenor any other suitable leaving group (e.g. trifluoromethylsulphonateetc.). Suitably LG_(A) may be chlorine, bromine ortrifluoromethylsulphonate.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of a suitable solvent. Any suitable solvent orsolvent mixture may be used for this reaction. A person skilled in theart will know how to select suitable solvents or solvent mixtures foruse in these reactions. Examples of suitable solvents include DMA,1,4-dioxane, toluene, DMF, tBuOH, THF and H₂O.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out an elevated temperature, such as, for example, within therange of 80 to 160° C. or, more suitably 100 to 160° C. (depending onthe solvent utilised), for a suitable time period of, for example, 2hours to 7 days, or more suitably 2 to 10 hours either thermally orunder microwave irradiation.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of a catalyst, suitably a palladium-derivedcatalyst, such as Pd or Pd₂(dba)₃ or by using an acid catalysis, such astrifluoroacetic acid.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of an organophosphorus compound, suitably anorganophosphorus compound which serves as a suitable ligand to thecatalyst. The organophosphorus compound may suitably be aphosphine-derivative, such as Xantphos.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of a base, for example a metal carbonate, such ascesium carbonate, or metal hydrides, such as sodium hydride.

The compound of formula A can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

The compound of formula B can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

A racemic compound of formula I may be separated using suitable chiralseparation chromatography to furnish the desired enantiomers.

In another aspect, the present invention provides a method ofsynthesising a compound of the formula I, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

a) reacting a compound of formula C:

wherein R₃ and R₄ each have any one of the meanings as definedhereinbefore;with a compound of formula B as defined hereinbefore, or a compound offormula D:

wherein R₁ and R₂ are as defined herein; andb) optionally thereafter, and if necessary:i) removing any protecting groups present;ii) converting the compound formula I into another compound of formulaI; and/oriii) forming a pharmaceutically acceptable salt or solvate thereof.

Suitably the coupling reaction between compound C and compound B or Dtakes place in the presence of a suitable solvent. Any suitable solventor solvent mixture may be used for this reaction. A person skilled inthe art will know how to select suitable solvents or solvent mixturesfor use in these reactions. Examples of suitable solvents include THF,TFE (1,2,3-trifluoroethanol) or DMF.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out an elevated temperature, such as, for example, within therange of 30 to 170° C. or, more suitably 30 to 50° C. for compounds offormula D and 120 to 170 50° C. for compounds of formula B (depending onthe solvent utilised), for a suitable time period of, for example, 2hours to 7 days, or more suitably 2 to 10 hours either thermally orunder microwave irradiation.

Suitably the coupling reaction between compound C and compounds B or Dtakes place in the presence of a catalyst, suitably a palladium-derivedcatalyst, such as Pd or Pd₂(dba)₃ or by using an acid catalysis, such astrifluoroacetic acid.

Suitably the coupling reaction between compound C and compounds B or Dtakes place in the presence of an organophosphorus compound, suitably anorganophosphorus compound which serves as a suitable ligand to thecatalyst. The organophosphorus compound may suitably be aphosphine-derivative, such as Xantphos.

Suitably the coupling reaction between compound C and compounds B or Dtakes place in the presence of a base, for example a metal carbonate,such as cesium carbonate, or metal hydrides, such as sodium hydride.

The compound of formula C can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

The compound of formula D can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

In another aspect, the present invention provides a method ofsynthesising a compound of the formula I, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

a) reacting a compound of formula E:

wherein R₁ and R₂ each have any one of the meanings as definedhereinbefore, and LG_(A) is a suitable leaving group as hereinbeforedefined;with a compound of formula F:

HNR₃R₄  Formula F

andb) optionally thereafter, and if necessary:i) removing any protecting groups present;ii) converting the compound formula I into another compound of formulaI; and/oriii) forming a pharmaceutically acceptable salt or solvate thereof.

As described above, LG_(A) may be any suitable leaving group. SuitablyLG_(A) is a halogen or any other suitable leaving group (e.g.trifluoromethylsulphonate etc.). Suitably LG_(A) may be chlorine orbromine.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of a suitable solvent. Any suitable solvent orsolvent mixture may be used for this reaction. A person skilled in theart will know how to select suitable solvents or solvent mixtures foruse in these reactions. Examples of suitable solvents include dioxane,DMA, NMP, THF, or TFE.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out an elevated temperature, such as, for example, within therange of 100 to 140° C. (depending on the solvent utilised), for asuitable time period of, for example, 2 hours to 7 days, or moresuitably 2 to 10 hours either thermally or under microwave irradiation.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of a catalyst, suitably a palladium-derivedcatalyst, such as Pd or Pd₂(dba)₃, Pd(PPh₃)₄ or Pd(dppf)Cl₂ or by usingan acid catalysis, such as trifluoroacetic acid.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of an organophosphorus compound, suitably anorganophosphorus compound which serves as a suitable ligand to thecatalyst. The organophosphorus compound may suitably be aphosphine-derivative, such as Xantphos or DavePhos.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of a base, for example a metal carbonate, such ascesium carbonate, or metal hydrides, such as sodium hydride.

The compound of formula E can be prepared by processes known in the artand/or by the processes described herein with reference to the examples.

The compound of formula F can be prepared by processes known in the art,and/or by the processes described herein with reference to the examples.

The resultant compound of formula I can be isolated and purified usingtechniques well known in the art.

The processes defined herein may further comprise the step of subjectingthe compound of formula I to a salt exchange, particularly in situationswhere the compound of formula I is formed as a mixture of different saltforms. The salt exchange suitably comprises immobilising the compound offormula I on a suitable solid support or resin, and eluting thecompounds with an appropriate acid to yield a single salt of thecompound of formula I.

In a further aspect of the invention, there is provided a compound offormula I obtainable by any one of the processes defined herein.

In a further aspect of the invention, there is provided a compound offormula I obtained by any one of the processes defined herein.

In a further aspect of the invention, there is provided a compound offormula I directly obtained by any one of the processes defined herein.

By way of example, particular synthetic schemes by which compounds ofthe invention can be prepared are shown below in Schemes 1 to 3:

Biological Activity

The following biological assays may be used to measure thepharmacological effects of the compounds of the present invention.

Measurement of Inhibition of MPS1 Kinase

The enzyme reaction (total volume 10 μl) was carried out in black384-well low volume plates containing full length MPS1 (12.5 nM or 3nM), fluorescent labelled peptide [known as H236, which has thesequence: 5FAM-DHTGFLTEYVATR-CONH₂] (5 μM), ATP (10 μM), either DMSO (1%v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) andassay buffer (50 mM HEPES (pH 7.0), 0.02% NaN₃, 0.01% BSA, 0.1 mMOrthovandate, 10 μM MgCl₂, 1 μM DTT, Roche protease inhibitor). Thereaction was carried out for 60 min at room temperature and stopped bythe addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v)Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The platewas read on a Caliper EZ reader II (Caliper Life Sciences).

The reader provides a Software package (‘Reviewer’) which converts thepeak heights into % conversion by measuring both product and substratepeak and also allows selection of control well which represent 0% and100% inhibition, respectively. The % inhibition of the compounds iscalculated relative to the means of selected control wells. IC₅₀s aredetermined by testing the compounds at a range of concentrations from0.25 nM-100 μM. The % inhibitions at each concentration are then fittedto a 4 parameter logistic fit:

y=(a+((b−a)/(1+((c/x̂d))))

where a=asym min, b=asym max, c=IC₅₀ and d=hill coefficient

In general, activity possessed by compounds of the formula I, may bedemonstrated in the inhibition assay by an IC₅₀ value of less than 15μM. Suitably compounds have an IC₅₀ value of less than 10 μM, suitablyless than 1 μM, suitably less than 0.1 μM, and suitably less than 0.01μM (i.e. less than 10 nM).

The activities of compounds of the invention in the above assay areshown in the accompanying example section.

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy of proliferative disease is an amount sufficient tosymptomatically relieve in a warm-blooded animal, particularly a humanthe symptoms of infection, to slow the progression of infection, or toreduce in patients with symptoms of infection the risk of getting worse.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

In one aspect, the present invention provides a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in therapy.

The compounds of the invention are capable of inhibiting Mps1 kinaseactivity.

Thus, in another aspect, the present invention provides a method ofinhibiting Mps1 kinase activity in a cell, the method comprisingadministering to said cell compound of formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a method ofinhibiting Mps1 kinase in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound, or apharmaceutically acceptable salt or solvate thereof, as defined herein.

In another aspect, the present invention provides a method of inhibitingMps1 kinase activity in a human or animal subject in need of suchinhibition, the method comprising administering to said subject aneffective amount of a compound of formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound of formulaI as defined herein, or a pharmaceutically acceptable salt or solvatethereof for use in the treatment of disease or condition associated withMps1 kinase activity.

In another aspect, the present invention provides the use of a compoundof formula I as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, in the manufacture of a medicament for use in thetreatment of disease or condition associated with Mps1 kinase activity.

In yet another aspect, the present invention provides a method oftreating a proliferative disorder in a human or animal subject, themethod comprising administering to said subject a therapeuticallyacceptable amount of a compound of formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In yet another aspect, the present invention provides a compound offormula I as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, for use in the treatment of a proliferative disorder.

In yet another aspect, the present invention provides the use of acompound of formula I as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor use in the treatment of a proliferative disorder.

The term “proliferative disorder” are used interchangeably herein andpertain to an unwanted or uncontrolled cellular proliferation ofexcessive or abnormal cells which is undesired, such as, neoplastic orhyperplasticgrowth, whether in vitro or in vivo. Examples ofproliferative conditions include, but are not limited to, pre-malignantand malignant cellular proliferation, including but not limited to,malignant neoplasms and tumours, cancers, leukemias, psoriasis, bonediseases, fibroproliferative disorders (e.g., of connective tissues),and atherosclerosis. Any type of cell may be treated, including but notlimited to, lung, colon, breast, ovarian, prostate, liver, pancreas,brain, and skin.

The anti-proliferative effects of the compounds of the present inventionhave particular application in the treatment of human cancers by virtueof their Mps1 kinase inhibitory properties.

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of angiogenesis (the formation of new blood vessels), theinhibition of metastasis (the spread of a tumour from its origin), theinhibition of invasion (the spread of tumour cells into neighbouringnormal structures), or the promotion of apoptosis (programmed celldeath).

Therefore, in another aspect, the present invention provides a compound,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in the treatment ofcancer.

In yet another aspect, the present invention provides the use of acompound, or a pharmaceutically acceptable salt or solvate thereof, asdefined herein in the manufacture of a medicament for use in thetreatment of cancer.

In yet another aspect, the present invention provides a method oftreating cancer in a patient in need of such treatment, said methodcomprising administering to said patient a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition as defined herein.

The invention further provides a method of treatment of the human oranimal body, the method comprising administering to a subject in need oftreatment a therapeutically-effective amount of an active compound,preferably in the form of a pharmaceutical composition.

Routes of Administration

The compounds of the invention or pharmaceutical composition comprisingthe active compound may be administered to a subject by any convenientroute of administration, whether systemically/peripherally or topically(ie. at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Combination Therapies

The antiproliferative treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) andbosutinib (SKI-606), and metalloproteinase inhibitors like marimastat,inhibitors of urokinase plasminogen activator receptor function orantibodies to Heparanase];(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin αvβ3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of a cancer (for example acancer involving a solid tumour) comprising a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, and another anti-tumour agent.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of a cancer (for example acancer involving a solid tumour) comprising a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, and any one of the anti-tumour agents listed under(i)-(ix) above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof, incombination with an anti-tumour agent selected from one listed under(i)-(ix) herein above.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt or solvate thereof in combinationwith an anti-tumour agent selected from one listed under (i)-(ix) hereinabove, in association with a pharmaceutically acceptable diluent orcarrier.

EXAMPLES General Experimental Methods

LC/MS analysis was performed on a Waters Alliance 2795 SeparationsModule and Waters 2487 dual wavelength absorbance detector coupled to aWaters/Micromass LCt time of flight mass spectrometer with ESI source.Analytical separation was carried out at 30° C. either on a MerckChromolith SpeedROD column (RP-18e, 50×4.6 mm) using a flow rate of 2mL/min in a 3.5 minute gradient elution with detection at 254 nm or on aMerck Purospher STAR column (RP-18e, 30×4 mm) using a flow rate of 1.5mL/min in a 3.5 minute gradient elution with detection at 254 nm. Themobile phase was a mixture of MeOH (solvent A) and water (solvent B)both containing formic acid at 0.1%. Gradient elution was as follows:1:9 (A/B) to 9:1 (A/B) over 2.25 min, 9:1 (A/B) for 0.75 min, and thenreversion back to 1:9 (A/B) over 0.3 min, finally 1:9 (A/B) for 0.2 min(ESI-HRMS Method A).

LC/MS and HRMS analyses were performed on an Agilent 1200 series HPLCand diode array detector coupled to a 6210 time of flight massspectrometer with dual multimode atmospheric pressure CI/ESI source.Analytical separation was carried out at 30° C. either on a MerckChromolith SpeedROD column (RP-18e, 50×4.6 mm) using a flow rate of 2mL/min in a 4 minute gradient elution with detection at 254 nm or on aMerck Purospher STAR column (RP-18e, 30×4 mm) using a flow rate of 1.5mL/min in a 4 minute gradient elution with detection at 254 nm. Themobile phase was a mixture of MeOH (solvent A) and water (solvent B)both containing formic acid at 0.1%. Gradient elution was: 1:9 (A/B) to9:1 (A/B) over 2.5 min, 9:1 (A/B) for 1 min, and then reversion back to1:9 (A/B) over 0.3 min, finally 1:9 (A/B) for 0.2 min (Default methodalso referred to as ESI-HRMS Method B). The following references masseswere used for HRMS analysis: caffeine [M+H]⁺ 195.087652;(hexakis(1H,1H,3H-tetrafluoropentoxy)phosphazene [M+H]⁺ 922.009798) andhexakis(2,2-difluoroethoxy)phosphazene [M+H]+ 622.02896 or reserpine[M+H]⁺ 609.280657.

LC/MS and HRMS analysis was also performed on a Waters Acquity UPLC anddiode array detector coupled to a Waters G2 QToF mass spectrometerfitted with a multimode ESI/APCI source. Analytical separation wascarried out at 30° C. on a Phenomenex Kinetex XB-C18 column (30×2.1 mm,1.7 u, 100 A) using a flow rate of 0.3 mL/min in a 4 minute gradientelution with detection at 254 nm. The mobile phase was a mixture ofmethanol (solvent A) and water containing formic acid at 0.1% (solventB). Gradient elution was as follows: 1:9 (A/B) to 9:1 (A/B) over 3 min,9:1 (A/B) for 0.5 min, and then reversion back to 1:9 (A/B) over 0.3min, finally 1:9 (A/B) for 0.2 min(also referred to ESI-HRMS Method C).The following references masses were used for HRMS analysis: LeucineEnkephalin fragment ion [M+H]⁺ 397.1876 [C₂₁H₂₅N₄O₄+H]⁺

General HPLC Methods

A) Fast2 mins: Analytical separation was carried out at 40° C. on aMerck Purospher STAR column (RP-18e, 30×4 mm) using a flow rate of 3mL/min in a 2 minute gradient elution with detection at 254 nm. Themobile phase was a mixture of methanol (solvent A) and water containingformic acid at 0.1% (solvent B). Gradient elution was as follows: 1:9(A/B) to 9:1 (A/B) over 1.25 min, 9:1 (A/B) for 0.5 min, and thenreversion back to 1:9 (A/B) over 0.15 min, finally 1:9 (A/B) for 0.1 min

B) Fast4 mins: Analytical separation was carried out at 30° C. on aMerck Purospher STAR column (RP-18e, 30×4 mm) using a flow rate of 1.5mL/min in a 4 minute gradient elution with detection at 254 nm. Themobile phase was a mixture of methanol (solvent A) and water containingformic acid at 0.1% (solvent B). Gradient elution was as follows: 1:9(A/B) to 9:1 (A/B) over 2.5 min, 9:1 (A/B) for 1 min, and then reversionback to 1:9 (A/B) over 0.3 min, finally 1:9 (A/B) for 0.2 min.

Example 1N2-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

Method 1

To a solution of6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 4, 29 mg, 0.094 mmol) in DMSO (7 mL) was addedN-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)formamide(Preparation 31, 22 mg, 0.094 mmol) and Cs₂CO₃ (61 mg, 0.188 mmol). Thereaction was heated to 100° C. for 18 hours. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified byelution through an SCX-2 cartridge using MeOH followed by 1M NH₃ in MeOHto afford the title compound (13.4 mg, 33%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.04 (s, 1H), 8.69 (d, J=8.5 Hz, 1H),7.84 (s, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.5, 2.0 Hz, 1H), 6.71(s, 1H), 4.16 (s, 3H), 4.05 (s, 3H), 3.47 (s, 2H), 2.44 (d, J=0.5 Hz,3H), 1.09 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₉N₈O [M+H]⁺ 433.2459, found 433.2449.

MPS1 IC50 (μM): 0.0005

Example 2N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine

To a solution of6-methyl-2-(methylsulfonyl)-N-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 5, 34 mg, 0.101 mmol) in DMSO (7 mL) was addedN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 32, 30 mg, 0.121 mmol) and Cs₂CO₃ (66 mg, 0.202 mmol). Thereaction was heated to 100° C. for 18 hours. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-10% MeOH in DCM followedby elution through an SCX-2 cartridge using MeOH followed by 1M NH₃ inMeOH to afford the title compound (27.6 mg, 58%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.06 (s, 1H), 8.82 (d, J=8.5 Hz, 1H),8.55 (s, 1H), 7.40-7.37 (m, 2H), 6.74 (s, 1H), 4.31 (q, J=7.0 Hz, 2H),4.08 (td, J=8.5, 5.0 Hz, 1H), 3.93-3.90 (m, 2H), 3.87 (s, 3H), 3.71 (d,J=13.5 Hz, 1H), 3.64 (d, J=13.5 Hz, 1H), 3.52 (d, J=8.5 Hz, 1H), 2.45(s, 3H), 2.08 (m, 1H), 1.82 (m, 1H), 1.56 (t, J=7.0 Hz, 3H), 1.29 (s,3H).

HRMS (ESI) MS m/z calcd for C₂₅H₃₁N₈O₂ [M+H]⁺ 475.2564, found 475.2549.

MPS1 IC50 (μM): 0.002

Example 31-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-3-methylazetidine-3-carbonitrile

To a solution of3-methyl-1-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)azetidine-3-carbonitrile(Preparation 7, 64 mg, 0.202 mmol) in DMSO (7 mL) was addedN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 32, 60 mg, 0.242 mmol) and Cs₂CO₃ (131 mg, 0.403 mmol). Thereaction was heated to 100° C. for 18 hours. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-10% MeOH in DCM followedby elution through an SCX-2 cartridge using MeOH followed by 1M NH₃ inMeOH to afford the title compound (34.6 mg, 38%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.10 (s, 1H), 8.56 (s, 1H), 8.46 (d,J=8.5 Hz, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H),6.91 (s, 1H), 4.75 (d, J=9.0 Hz, 2H), 4.39 (d, J=9.0 Hz, 2H), 4.28 (q,J=7.0 Hz, 2H), 3.88 (s, 3H), 2.47 (s, 3H), 1.75 (s, 3H), 1.53 (t, J=7.0Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₆N₉O [M+H]⁺ 456.2255, found 456.2180.

MPS1 IC50 (μM): 0.003

Example 4N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine

To a solution of2-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa-2-azaspiro[3.5]nonane(Preparation 8, 15 mg, 0.044 mmol) in DMSO (4 ml) was addedN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 32, 13 mg, 0.052 mmol) and Cs₂CO₃ (28 mg, 0.087 mmol). Thereaction was heated to 100° C. for 18 hours. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-10% MeOH in DCM followedby elution through an SCX-2 cartridge using MeOH followed by 1M NH₃ inMeOH to afford the title compound (9.7 mg, 46%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.06 (s, 1H), 8.57 (d, J=8.5 Hz, 1H),8.56 (s, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.5, 2.0 Hz, 1H), 6.78(s, 1H), 4.31-4.27 (m, 6H), 3.87 (s, 3H), 3.69 (app t, J=5.5 Hz, 4H),2.44 (s, 3H), 1.89 (app t, J=5.5 Hz, 4H), 1.54 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₆H₃₁N₈O₂ [M+H]⁺ 487.2564, found 487.2511.

MPS1 IC50 (μM): 0.002

Example 51-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)piperidine-4-carbonitrile

To a solution of1-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)piperidine-4-carbonitrile(Preparation 9, 22 mg, 0.067 mmol) in DMSO (5 mL) was addedN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 32, 20 mg, 0.081 mmol) and Cs₂CO₃ (44 mg, 0.135 mmol). Thereaction was heated to 100° C. for 18 hours. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-10% MeOH in DCM followedby elution through an SCX-2 cartridge using MeOH followed by 1M NH₃ inMeOH to afford the title compound (14.7 mg, 47%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.16 (s, 1H), 8.84 (d, J=8.5 Hz, 1H),8.56 (s, 1H), 7.41-7.39 (m, 2H), 7.07 (s, 1H), 4.31 (q, J=7.0 Hz, 2H),4.20-4.15 (m, 2H), 3.89 (s, 3H), 3.69-3.64 (m, 2H), 3.10 (m, 1H), 2.51(s, 3H), 2.24-2.18 (m, 2H), 2.12-2.07 (m, 2H), 1.56 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₅H₂₈N₉O [M+H]⁺ 470.2411, found 470.2394.

MPS1 IC50 (μM): 0.003

Example 6N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine

To a solution of6-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 12, 19 mg, 0.059 mmol) in DMSO (5 mL) was addedN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 32, 17 mg, 0.071 mmol) and Cs₂CO₃ (38 mg, 0.118 mmol). Thereaction was heated to 100° C. for 18 hours. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-10% MeOH in DCM followedby elution through an SCX-2 cartridge using MeOH followed by 1M NH₃ inMeOH to afford the title compound (15 mg, 55%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.06 (s, 1H), 8.70 (d, J=9.0 Hz, 1H),8.56 (s, 1H), 7.41-7.38 (m, 2H), 6.75 (d, J=0.5 Hz, 1H), 4.60 (br s,2H), 4.36 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 4.03 (dt, J=12.0, 2.5 Hz,1H), 3.88 (s, 3H), 3.65 (td, J=12.0, 2.5 Hz, 1H), 2.45 (d, J=0.5 Hz,3H), 2.16-2.12 (m, 2H), 1.77-1.69 (m, 2H), 1.56 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₈O₂ [M+H]⁺ 461.2408, found 461.2388.

MPS1 IC50 (μM): 0.005

Example 7N2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

To 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 4, 20 mg, 0.063 mmol) was added Cs₂CO₃ (28 mg, 0.086 mmol)and N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 43, 15 mg, 0.058 mmol) in DMSO (2.0 ml). The reaction washeated to 100° C. for 18 hours. The reaction mixture was diluted withEtOAc and water. The aqueous layer was re-extracted with EtOAc and thecombined organic layers were dried (MgSO₄) and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 0-10% MeOH in DCM followed by elution through an SCX-2 cartridgeusing MeOH followed by 1M NH₃ in MeOH to afford the title compound (14.8mg, 56%)

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.06 (s, 1H), 8.75 (d, J=8.5 Hz, 1H),7.34 (d, J=1.9 Hz, 1H), 7.28 (dd, J=8.5, 1.9 Hz, 1H), 6.72 (s, 1H), 4.30(q, J=7.2 Hz, 1H), 3.71 (s, 3H), 3.48 (s, 2H), 2.53 (s, 3H), 2.45 (s,3H), 1.56 (t, J=7.2 Hz, 3H), 1.10 (s, 9H).

HRMS (ESI) MS m/z calcd C₂₅H₃₃N₈O [M+H]⁺ 461.2772, found 461.2756.

MPS1 IC50 (μM): 0.004

Examples 8 to 26

The following Examples were prepared according to Method 1 (Example 1)above using the appropriate methylsulfonylpyridopyrimidine and theappropriate formamide as described. The crude reaction residues werepurified as above or according to one of the following PurificationMethods (PM):

Purification Method A: Silica gel column chromatography eluting with0-10% MeOH in DCM followed by elution through an SCX-2 cartridge usingMeOH followed by 1M NH₃ in MeOH.

Purification Method B: Silica gel column chromatography eluting with0-10% MeOH in DCM.

Purification Method C: Silica gel column chromatography eluting with0-30% EtOAc in cyclohexane.

Purification Method D: Silica gel column chromatography eluting with0-5% MeOH in DCM.

Purification Method E: Silica gel column chromatography eluting with0-10% MeOH in DCM followed by silica gel column chromatography elutingwith 0-10% MeOH in EtOAc followed by elution through an SCX-2 cartridgeusing MeOH followed by 1M NH₃ in MeOH.

Purification Method F: Silica gel column chromatography eluting with0-10% MeOH in DCM followed by silica gel column chromatography elutingwith 3-10% MeOH in DCM.

MPS1 Example IC50 No Name/Structure Data (μM) 8 1-(((2-((2-ethoxy-4-(4-¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.003 methyl-4H-1,2,4-triazol-3- 9.07(s, 1H), 8.80 (d, J = 8.5 Hz, 1H), yl)phenyl)amino)-6- 8.56 (s, 1H),7.39 (dd, J = 8.5, 2.0 Hz, methylpyrido[3,4- 1H), 7.38 (d, J = 2.0 Hz,1H), 6.76 (d, J = d]pyrimidin-8- 0.5 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H),yl)amino)methyl) 3.88 (s, 3H), 3.78 (s, 2H), 2.45 (d, J = 0.5cyclobutanol  

Hz, 3H), 2.22-2.10 (m, 4H), 1.80 (m, 1H), 1.68 (m, 1H), 1.56 (t, J = 7.0Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₈O₂ [M + H]⁺ 461.2408, found461.2391. Using 1-(((6-methyl-2- (methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclobutanol (Preparation 6) and N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)formamide (Preparation 32). PM A. 91-(2-((2-ethoxy-4-(4- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.004methyl-4H-1,2,4-triazol-3- 9.06 (s, 1H), 8.55 (s, 1H), 8.54 (d, J = 8.5yl)phenyl)amino)-6- Hz, 1H), 7.39-7.36 (m, 2H), 6.80 (d, J =methylpyrido[3,4- 0.5 Hz, 1H), 4.44-4.40 (m, 2H), 4.38-d]pyrimidin-8-yl)-3- 4.34 (m, 2H), 4.29 (q, J = 7.0 Hz, 2H),methylazetidin-3-ol  

3.87 (s, 3H), 2.45 (d, J = 0.5 Hz, 3H), 1.57 (s, 3H), 1.54 (t, J = 7.0Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₃H₂₇N₈O₂ [M + H]⁺ 447.2251, found447.2207. Using 3-methyl-1-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin- 8-yl)azetidin-3-ol (Preparation10) and N-(2-ethoxy-4-(4-methyl-4H-1,2,4- triazol-3-yl)phenyl)formamide(Preparation 32). PM A. 10 N2-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz,MeOH-d₄): δ ppm No data 4H-1,2,4-triazol-3- 9.21 (s, 1H), 8.63 (d, J =8.5 Hz, 1H), yl)phenyl)-6-methyl-N8- 8.57 (s, 1H), 7.41 (s, 1H), 7.40(dd, J = ((3-methyloxetan-3- 8.5, 2.0 Hz, 1H), 7.05 (s, 1H), 4.32 (d, J= yl)methyl)pyrido[3,4- 13.5 Hz, 1H), 4.30, (q, J = 7.0 Hz, 2H),d]pyrimidine-2,8-diamine  

4.05 (dd, J = 13.5, 1.0 Hz, 1H), 3.88 (s, 3H), 3.69 (dd, J = 13.5, 1.0Hz, 1H), 3.55 (d, J = 2.5 Hz, 2H), 3.47 (dd, J = 13.5, 1.0 Hz, 1H), 2.61(s, 3H), 1.53 (t, J = 7.0 Hz, 3H), 1.19 (s, 3H). HRMS (ESI) MS m/z calcdfor C₂₄H₂₉N₈O₂ [M + H]⁺ 461.2408, found 461.2407. Using6-methyl-N-((3-methyloxetan-3- yl)methyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 11) andN-(2-ethoxy-4-(4-methyl-4H-1,2,4- triazol-3-yl)phenyl)formamide(Preparation 32). PM A. 11 N2-(2-methoxy-4-(1- ¹H NMR (500 MHz,MeOH-d₄): δ ppm 0.036 methyl-1H-pyrazol-3- 9.00 (s, 1H), 8.52 (d, J =8.5 Hz, 1H), yl)phenyl)-6-methyl-N8- 7.62 (d, J = 2.0 Hz, 1H), 7.50 (d,J = 2.0 neopentylpyrido[3,4- Hz, 1H), 7.39 (dd, J = 8.5, 2.0 Hz, 1H),d]pyrimidine-2,8-diamine  

6.69 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.46(s, 2H), 2.44 (s, 3H), 1.11 (s, 9H). HRMS (ESI) MS m/z calcd forC₂₄H₃₀N₇O [M + H]⁺ 432.2506, found 432.2487. Using6-methyl-2-(methylsulfonyl)-N- neopentylpyrido[3,4-d]pyrimidin-8- amine(Preparation 4) and N-(2- methoxy-4-(1-methyl-1H-pyrazol-3-yl)phenyl)formamide (Preparation 33). PM A. 12 N2-(2-methoxy-4-(1- ¹HNMR (500 MHz, MeOH-d₄): δ ppm 0.004 methyl-1H-imidazol-2- 9.03 (s, 1H),8.66 (d, J = 8.5 Hz, 1H), yl)phenyl)-6-methyl-N8- 7.32 (d, J = 2.0 Hz,1H), 7.24 (dd, J = neopentylpyrido[3,4- 8.5, 2.0 Hz, 1H), 7.19 (d, J =1.5 Hz, 1H), d]pyrimidine-2,8-diamine  

7.05 (d, J = 1.5 Hz, 1H), 6.70 (d, J = 0.5 Hz, 1H), 4.05 (s, 3H), 3.82(s, 3H), 3.46 (s, 2H), 2.44 (d, J = 0.5 Hz, 3H), 1.09 (s, 9H). HRMS(ESI) MS m/z calcd for C₂₄H₃₀N₇O [M + H]⁺ 433.2535, found 433.2512.Using 6-methyl-2-(methylsulfonyl)-N- neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 4) and N-(2- methoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)formamide (Preparation 34). PM B. 13 N2-(2-methoxy-4-(1- ¹HNMR (500 MHz, MeOH-d₄): δ ppm 0.018 methyl-1H-pyrazol-5- 9.03 (s, 1H),8.62 (d, J = 8.5 Hz, 1H), yl)phenyl)-6-methyl-N8- 7.52 (d, J = 2.0 Hz,1H), 7.16 (d, J = 2.0 neopentylpyrido[3,4- Hz, 1H), 7.09 (dd, J = 8.5,2.0 Hz, 1H), d]pyrimidine-2,8-diamine  

6.70 (d, J = 0.5 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 4.03 (s, 3H), 3.92(s, 3H), 3.46 (s, 2H), 2.44 (d, J = 0.5 Hz, 3H), 1.09 (s, 9H). HRMS(ESI) MS m/z calcd for C₂₄H₃₀N₇O [M + H]⁺ 432.2506, found 432.2503.Using 6-methyl-2-(methylsulfonyl)-N- neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 4) and N-(2- methoxy-4-(1-methyl-1H-pyrazol-5-yl)phenyl)formamide (Preparation 35). PM B. 14 N2-(2-methoxy-4-(oxazol-¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.059 2-yl)phenyl)-6-methyl-N8- 9.04(s, 1H), 8.71 (d, J = 8.5 Hz, 1H), neopentylpyrido[3,4- 7.98 (d, J = 1.0Hz, 1H), 7.70 (d, J = 2.0 d]pyrimidine-2,8-diamine  

Hz, 1H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 (d, J = 1.0 Hz, 1H), 6.70(d, J = 0.5 Hz, 1H), 4.08 (s, 3H), 3.48 (s, 2H), 2.44 (d, J = 0.5 Hz,3H), 1.12 (s, 9H). HRMS (ESI) MS m/z calcd for C₂₃H₂₇N₆O₂ [M + H]⁺419.219, found 419.217. Using 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8- amine (Preparation 4) and N-(2-methoxy-4-(oxazol-2- yl)phenyl)formamide (Preparation 36). PM B. 15N2-(2-(difluoromethoxy)-4- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.001(4-methyl-4H-1,2,4-triazol- 9.16 (s, 1H), 9.15 (s, 1H), 8.59 (s, 1H),3-yl)phenyl)-6-methyl-N8- 8.39 (d, J = 8.4 Hz, 1H), 7.67-7.60 (m,neopentylpyrido[3,4- 2H), 7.28 (t, J = 73.5 Hz, 1H), 6.72 (s,d]pyrimidine-2,8-diamine  

1H), 6.63 (t, J = 6.2 Hz, 1H), 3.78 (s, 3H), 3.37 (d, J = 6.0 Hz, 2H),2.36 (s, 3H), 0.97 (s, 9H). HRMS (ESI) MS m/z calcd for C₂₃H₂₇F₂N₈O [M +H]⁺ 469.2276, found 469.2263. Using 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8- amine (Preparation 4) and N-(2-(Difluoromethoxy)-4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)formamide(Preparation 38). PM C. 16 N2-(2-methoxy-4-(1- ¹H NMR (500 MHz,DMSO-d₆): δ ppm 0.005 methyl-1H-tetrazol-5- 9.17 (s, 1H), 8.66 (s, 1H),8.58 (d, J = 8.4 yl)phenyl)-6-methyl-N8- Hz, 1H), 7.51 (d, J = 1.9 Hz,1H), 7.46 neopentylpyrido[3,4- (dd, J = 8.4, 1.9 Hz, 1H), 6.75-6.67 (m,d]pyrimidine-2,8-diamine  

2H), 4.21 (s, 3H), 3.99 (s, 3H), 3.39 (d, J = 6.2 Hz, 2H), 2.36 (d, J =0.8 Hz, 3H), 0.99 (s, 9H). HRMS (ESI) MS m/z calcd for C₂₂H₂₈N₉O [M +H]⁺ 434.2417, found 434.2406. Using 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8- amine (Preparation 4) and N-(2-methoxy-4-(1-methyl-1H-tetrazol-5- yl)phenyl)formamide (Preparation 39)PM D. 17 N2-(4-(2,4-dimethyloxazol- ¹H NMR (500 MHz, MeOH-d₄): δ ppm0.043 5-yl)-2-methoxyphenyl)-6- 8.97 (s, 1H), 8.55 (d, J = 8.5 Hz, 1H),methyl-N8- 7.21 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), neopentylpyrido[3,4-6.66 (d, J = 0.5 Hz, 1H), 4.02 (s, 3H), d]pyrimidine-2,8-diamine  

3.45 (s, 2H), 2.49 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H), 1.10 (s, 9H).HRMS (ESI) MS m/z calcd for C₂₅H₃₁N₆O₂ [M + H]⁺ 447.2508, found447.2508. Using 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8- amine (Preparation 4) and N-(4-(2,4-dimethyloxazol-5-yl)-2- methoxyphenyl)formamide (Preparation 40). PM A.18 N2-(4-(1,5-dimethyl-1H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.004imidazol-2-yl)-2- 9.02 (s, 1H), 8.64 (d, J = 8.5 Hz, 1H),methoxyphenyl)-6-methyl- 7.28 (d, J = 2.0 Hz, 1H), 7.19 (dd, J =N8-neopentylpyrido[3,4- 8.5, 2.0 Hz, 1H), 6.83 (d, J = 1.0 Hz, 1H),d]pyrimidine-2,8-diamine  

6.69 (d, J = 0.5 Hz, 1H), 4.04 (s, 3H), 3.68 (s, 3H), 3.48 (s, 2H), 2.43(d, J = 0.5 Hz, 3H), 2.32 (d, J = 1.0 Hz, 3H), 1.09 (s, 9H). HRMS (ESI)MS /z calcd for C₂₅H₃₂N₇O [M + H]⁺ 446.2668, found 446.2670. Using6-methyl-2-(methylsulfonyl)-N- neopentylpyrido[3,4-d]pyrimidin-8- amine(Preparation 4) and N-(4-(1,5- dimethyl-1H-imidazol-2-yl)-2-methoxyphenyl)formamide (Preparation 41). PM A. 19N-(4-(1,2-dimethyl-1H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.005imidazol-5-yl)-2- 9.00 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H),methoxyphenyl)-8-(3,3- 7.06 (d, J = 1.7 Hz, 1H), 7.03 (dd, J =dimethylazetidin-1-yl)-6- 8.3, 1.7 Hz, 1H), 6.90 (br s, 1H), 6.74 (s,methylpyrido[3,4- 1H), 4.18 (br s, 4H), 3.99 (s, 3H), 3.62d]pyrimidin-2-amine  

(s, 3H), 2.45 (s, 3H), 2.43 (s, 3H), 1.36 (s, 6H). HRMS (ESI) MS m/zcalcd C₂₅H₃₀N₇O [M + H]⁺ 444.2512, found 444.2516 Using8-(3,3-dimethylazetidin-1-yl)-6- methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 13) and N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2- methoxyphenyl)formamide (Preparation37) at 120° C. for 18 hours. PM A. 20 N-(4-(1,2-dimethyl-1H- ¹H NMR (500MHz, MeOH-d₄): δ ppm 0.012 imidazol-5-yl)-2- 9.01 (s, 1H), 8.32 (d, J =8.1 Hz, 1H), methoxyphenyl)-6-methyl- 7.08 (d, J = 1.6 Hz, 1H), 7.05(dd, J = 8-(7-oxa-2- 8.1, 1.6 Hz, 1H), 6.90 (s, 1 H), 6.75 (s,azaspiro[3.5]nonan-2- 1H), 4.25 (br s, 4H), 3.90 (s, 3H), 3.69-yl)pyrido[3,4-d]pyrimidin-2- 3.66 (m, 4H), 3.63 (s, 3H), 2.45 (s, 3H),amine  

2.43 (s, 3H), 1.87 (app t, J = 5.3 Hz, 4H). HRMS (ESI) MS m/z calcdC₂₇H₃₁N₇O₂ [M + H]⁺ 486.2617, found 486.2623. Using 2-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa-2-azaspiro[3.5]nonane (Preparation 8) andN-(4-(1,2-dimethyl- 1H-imidazol-5-yl)-2- methoxyphenyl)formamide(Preparation 37) at 120° C. for 18 hours. PM E. 21N2-(4-(4,5-dimethyl-4H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.0011,2,4-triazol-3-yl)-2- 9.04 (s, 1H), 8.74 (d, J = 8.3 Hz, 1H),methoxyphenyl)-6-methyl- 7.36 (d, J = 1.9 Hz, 1H), 7.28 (dd, J =N8-neopentylpyrido[3,4- 8.3, 1.9 Hz, 1H), 6.71 (d, J = 0.6 Hz,d]pyrimidine-2,8-diamine  

1H), 4.06 (s, 3H), 3.72 (s, 3H), 3.47 (s, 2H), 2.54 (s, 3H), 2.44 (d, J= 0.6 Hz, 3H), 1.09 (s, 9H). HRMS (ESI) MS m/z calcd C₂₄H₃₁N₈O [M + H]⁺447.2621, found 447.2626. Using 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8- amine (Preparation 4) and N-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2- methoxyphenyl)formamide (Preparation37) at 120° C. for 18 hours. PM A. 22 N-(4-(4,5-dimethyl-4H- ¹H NMR (500MHz, MeOH-d₄): δ ppm 0.02  1,2,4-triazol-3-yl)-2- 9.06 (s, 1H), 8.50 (d,J = 8.2 Hz, 1H), ethoxyphenyl)-8-(3,3- 7.31 (d, J = 1.6 Hz, 1H), 7.28(dd, J = dimethylazetidin-1-yl)-6- 8.2, 1.6 Hz, 1H), 6.77 (s, 1H), 4.28(q, methylpyrido[3,4- J = 6.9 Hz, 2H) 4.24 (br s, 4H), 3.71 (s,d]pyrimidin-2-amine  

3H), 2.54 (s, 3H), 2.44 (s, 3H), 1.53 (t, J = 6.9 Hz, 3H), 1.38 (s, 6H).HRMS (ESI) MS m/z calcd C₂₅H₃₁N₈O [M + H]⁺ 459.2621, found 459.2660.Using 8-(3,3-dimethylazetidin-1-yl)-6-methyl-2-(methylsulfonyl)pyrido[3,4- d]pyrimidine (Preparation 13) andN-(4- (4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2- ethoxyphenyl)formamide(Preparation 43) at 120° C. for 18 hours. PM A. 23N-(4-(4,5-dimethyl-4H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.0041,2,4-triazol-3-yl)-2- 9.05 (s, 1H), 8.56 (d, J = 8.2 Hz, 1H),ethoxyphenyl)-6-methyl-8- 7.32 (d, J = 1.8 Hz, 1H), 7.30 (dd, J =(7-oxa-2- 8.2, 1.8 Hz, 1H), 6.78 (s, 1H), 4.31-4.26azaspiro[3.5]nonan-2- (m, 6H), 3.72 (s, 3H), 3.69 (app t, J = 5.0yl)pyrido[3,4-d]pyrimidin-2- Hz, 4H), 2.54 (s, 3H), 2.44 (s, 3H), 1.89amine  

(app t, J = 5.0 Hz, 4H), 1.54 (t, J = 7.0 Hz, 3H). HRMS (ESI) MS m/zcalcd C₂₇H₃₃N₈O₂ [M + H]⁺ 501.2726, found 501.2726. Using 2-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa-2-azaspiro[3.5]nonane (Preparation 8) andN-(4-(4,5-dimethyl- 4H-1,2,4-triazol-3-yl)-2- ethoxyphenyl)formamide(Preparation 43) at 120° C. for 18 hours. PM B. 24N-(2-ethoxy-4-(4-ethyl-4H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.0021,2,4-triazol-3-yl)phenyl)- 9.06 (s, 1H), 8.67 (s, 1H), 8.57 (d, J = 8.26-methyl-8-(7-oxa-2- Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H), 7.29azaspiro[3.5]nonan-2- (dd, J = 8.2, 1.7 Hz, 1H), 6.78 (s, 1H),yl)pyrido[3,4-d]pyrimidin-2- 4.30-4.23 (m, 8H), 3.70-3.68 (m, 4H), amine 

2.44 (s, 3H), 1.89 (br t, J = 5.2 Hz, 4H), 1.54 (t, J = 7.0 Hz, 3H),1.46 (t, J = 7.4 Hz, 3H). HRMS (ESI) MS m/z calcd C₂₇H₃₃N₈O₂ [M + H]⁺501.2721, found 501.2706 Using 2-(6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa-2-azaspiro[3.5]nonane (Preparation 8) and N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3- yl)phenyl)formamide (Preparation 44). PM F. 258-(3,3-dimethylazetidin-1- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.006yl)-N-(2-ethoxy-4-(4-ethyl- 9.05 (s, 1H), 8.67 (s, 1H), 8.55 (d, J = 8.34H-1,2,4-triazol-3- Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.28yl)phenyl)-6- (dd, J = 8.3, 1.7 Hz, 1H), 6.77 (s,1 H), methylpyrido[3,4-4.30-4.21 (m, 8H), 2.44 (s, 3H), 1.54 (t, d]pyrimidin-2-amine  

J = 7.0 Hz, 3H), 1.44 (t, J = 7.4 Hz, 3H), 1.37 (s, 6H). HRMS (ESI) MSm/z calcd C₂₅H₃₁N₈O [M + H]⁺ 459.2615, found 459.2601. Using8-(3,3-dimethylazetidin-1-yl)-6- methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 13) and N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3- yl)phenyl)formamide (Preparation44). PM A. 26 N2-(2-ethoxy-4-(4-ethyl- ¹H NMR (500 MHz, MeOH-d₄): δ ppm0.006 4H-1,2,4-triazol-3- 9.06 (s, 1H), 8.77 (d, J = 8.4 Hz, 1H),yl)phenyl)-6-methyl-N8- 8.66 (s, 1H), 7.34 (d, J = 1.7 Hz, 1H),neopentylpyrido[3,4- 7.27 (dd, J = 8.4, 1.7 Hz, 1H), 6.72 (s,d]pyrimidine-2,8-diamine  

1H), 4.30 (q, J = 7.0 Hz, 2H), 4.24 (q, J = 7.4 Hz, 2H), 3.48 (s, 2H),2.44 (s, 3H), 1.56 (t, J = 7.0 Hz, 3H), 1.44 (t, J = 7.4 Hz, 3H), 1.10(s, 9H). HRMS (ESI) MS m/z calcd C₂₅H₃₃N₈O [M + H]⁺ 461.2772, found461.2752. Using 6-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8- amine (Preparation 4) and N-(2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3- yl)phenyl)formamide (Preparation44). PM A.

Example 27N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine

Method 2

To a solution of8-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 1, 25 mg, 0.063 mmol) in NMP (3 mL) was added2-oxa-7-azaspiro[4.4]nonane (16 mg, 0.126 mmol) and triethylamine (0.044mL, 0.316 mmol). The reaction was heated to 100° C. in a closed cap vialfor 18 hours. The reaction mixture was diluted with EtOAc and water. Theorganic layer was washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 0-50% EtOAc in cyclohexane to afford the title compound(20.4 mg, 66%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.03 (s, 1H), 8.56 (s, 1H), 8.50 (d,J=8.5 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.5, 2.0 Hz, 1H),6.75 (s, 1H), 4.28 (q, J=7.0 Hz, 2H), 4.17-4.14 (m, 2H), 4.07-4.01 (m,2H), 3.96-3.88 (m, 2H), 3.87 (s, 3H), 3.74 (ABq, J=9.0 Hz, 2H), 2.44 (s,3H), 2.08-1.98 (m, 4H), 1.54 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₆H₃₁N₈O₂ [M+H]+ 487.2564, found 487.2572.

MPS1 IC50 (μM): 0.004

Example 281-(2-((2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyrido[3,4-d]pyrimidin-8-yl)-4-methylpiperidine-4-carbonitrile

To a solution of8-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 1, 25 mg, 0.063 mmol) in NMP (2 mL) was added4-methylpiperidine-4-carbonitrile (20 mg, 0.126 mmol) and triethylamine(0.044 mL, 0.316 mmol).

The reaction was heated to 100° C. in a closed cap vial for 18 hours.Further 4-methylpiperidine-4-carbonitrile hydrochloride (40 mg, 0.252mmol) was added and the reaction heated at 120° C. for a further 5hours. The reaction mixture was diluted with EtOAc and water. Theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by silica gel column chromatography eluting with 0-50%EtOAc in cyclohexane followed by elution through an SCX-2 cartridgeusing MeOH followed by 1M NH₃ in MeOH. The residue was further purifiedby silica gel column chromatography eluting with 0-15% MeOH in EtOAcfollowed by elution through an SCX-2 cartridge using MeOH followed by 1MNH₃ in MeOH to afford the title compound (5.1 mg, 17%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.13 (s, 1H), 8.80 (d, J=8.5 Hz, 1H),8.56 (s, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.5, 2.0 Hz, 1H), 7.04(s, 1H), 4.70 (br d, J=13.0 Hz, 2H), 4.29 (q, J=7.0 Hz, 2H), 3.88 (s,3H), 3.26 (t, J=13.0 Hz, 2H), 2.50 (s, 3H), 2.10 (br d, J=13.0 Hz, 2H),1.92 (td, J=13.0, 3.5 Hz, 2H), 1.56 (t, J=7.0 Hz, 3H), 1.51 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₆H₃₁N₉O [M+2H]/2⁺ 242.632, found 242.6321.

MPS1 IC50 (μM): 0.002

Example 298-(3,3-dimethylazetidin-1-yl)-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

To a solution of8-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 1, 20 mg, 0.051 mmol) in NMP (1 mL) was added3,3-dimethylazetidine hydrochloride (25 mg, 0.202 mmol) andtriethylamine (0.057 mL, 0.404 mmol). The reaction was heated to 100° C.in a closed cap vial for 18 hours. The reaction was diluted with EtOAcand water. The aqueous layer was re-extracted with EtOAc and thecombined organic layers were dried (MgSO₄) and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 0-10% MeOH in DCM to afford the title compound (15.7 mg, 70%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.05 (s, 1H), 8.56 (d, J=8.5 Hz, 1H),8.56 (s, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.34 (dd, J=8.5, 1.5 Hz, 1H), 6.77(s, 1H), 4.29 (q, J=7.0 Hz, 2H), 4.21 (br s, 4H), 3.87 (s, 3H), 2.44 (s,3H), 1.54 (t, J=7.0 Hz, 3H), 1.38 (s, 6H).

HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₈O [M+2H]/2⁺ 223.1266, found223.1261.

MPS1 IC50 (μM): 0.002

Example 30N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

A mixture of8-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 1, 26 mg, 0.066 mmol), triethylamine (110 μL, 0.795 mmol)and 3-methoxy-3-methylazetidine hydrochloride (48 mg, 0.349 mmol) in NMP(0.5 mL) was stirred at 130° C. in a closed cap vial for 18 hours. Thereaction was quenched with saturated aqueous NaHCO₃ solution andextracted with EtOAc. The combined organic layers were washed with waterand brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 0-5% MeOH inDCM to afford the title compound (18 mg, 60%).

¹H NMR (500 MHz, DMSO-d₆): δ ppm 9.17 (s, 1H), 8.57 (s, 1H), 8.45 (s,1H), 8.25 (d, J=8.2 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.36 (dd, J=8.2,1.8 Hz, 1H), 6.84 (s, 1H), 4.33-4.18 (br m, 4H), 4.15 (br d, J=8.6 Hz,2H), 3.78 (s, 3H), 3.21 (s, 3H), 2.38 (s, 3H), 1.46 (s, 3H), 1.40 (t,J=6.9 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₈O₂ [M+H]⁺ 461.2408, found 461.2385.

MPS1 IC50 (μM): 0.002

Examples 31 to 62

The following Examples were prepared according to Method 2 (Example 27)above using either8-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 1) or8-chloro-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 2) or8-chloro-N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 3) and the appropriate amine as described. Where necessaryfurther equivalents of amine were added and/or the reaction continuedheating to enable maximum yields. The crude reaction residues werepurified as above or according to one of the following PurificationMethods (PM): Purification Method A: Silica gel column chromatographyeluting with 0-10% MeOH in DCM or EtOAc followed by furtherchromatography eluting with 0-20% MeOH in EtOAc.

Purification Method B: Following the described chromatography theresidue was eluted through an SCX-2 cartridge using MeOH followed by 1MNH₃ in MeOH followed by further silica gel column chromatography elutingwith 0-10% MeOH in DCM.Purification Method C: Following the described chromatography theresidue was eluted through an SCX-2 cartridge using MeOH followed by 1MNH₃ in MeOH.Purification Method D: Reverse phase column chromatography eluting withwater followed by elution through an SCX-2 cartridge using MeOH followedby 1M NH₃ in MeOH.Purification Method E: Silica gel column chromatography eluting with0-10% MeOH in DCM followed by elution through an SCX-2 cartridge usingMeOH followed by 1M NH₃ in MeOH.Purification Method F: Silica gel column chromatography eluting with0-10% MeOH in DCM or EtOAc.Purification Method G: Silica gel column chromatography eluting with0-5% MeOH in DCM.

MPS1 Example IC50 No Name/Structure Data (μM) 31 1-(((2-((2-ethoxy-4-(4-¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.008 methyl-4H-1,2,4-triazol-3- 9.05(s, 1H), 8.79 (d, J = 9.0 Hz, 1H), yl)phenyl)amino)-6- 8.55 (s, 1H),7.40-7.37 (m, 2H), 6.74 (s, methylpyrido[3,4- 1H), 4.30 (q, J = 7.0 Hz,2H), 3.87 (s, d]pyrimidin-8- 3H), 3.75 (s, 2H), 2.42 (s, 3H), 1.56 (t,yl)amino)methyl) J = 7.0 Hz, 3H), 0.82-0.79 (m, 2H), 0.77- cyclopropanol 

0.74 (m, 2H). HRMS (ESI) MS m/z calcd for C₂₃H₂₇N₈O₂ [M + H]⁺ 448.2279,found 44.2283. Using (1-aminomethyl)cyclopropanol. PM A. 32N2-(4-(1,2-dimethyl-1H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.002imidazol-5-yl)-2- 9.02 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H),methoxyphenyl)-6-methyl- 7.09-7.07 (m, 2H), 6.90 (s, 1H), 6.72 (s,N8-((3- 1H), 4.06 (td, J = 8.5, 5.5 Hz, 1H), 4.02methyltetrahydrofuran-3- (s, 3H), 3.93-3.88 (m, 2H), 3.63 (s, 3H),yl)methyl)pyrido[3,4- 3.63 (d, J = 13.5 Hz, 1H), 3.69 (d, J =d]pyrimidine-2,8-diamine  

13.5 Hz, 1H), 3.52 (d, J = 8.5 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.06(m, 1H), 1.81 (m, 1H), 1.28 (s, 3H). HRMS (ESI) MS m/z calcd forC₂₆H₃₃N₇O₂ [M + 2H]/2⁺ 237.6342, found 237.6345. Using(3-methyltetrahydrofuran-3- yl)methanamine for 60 hours. PM B. 33N-(4-(1,2-dimethyl-1H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.005imidazol-5-yl)-2- 8.99 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H),methoxyphenyl)-6-methyl- 7.06 (d, J = 1.5 Hz, 1H), 7.04 (dd, J =8-(2-oxa-7- 8.0, 1.5 Hz, 1H), 6.90 (s, 1H), 6.72 (s,azaspiro[4.4]nonan-7- 1H), 4.11 (q, J = 8.5 Hz, 2H), 4.04-3.97yl)pyrido[3,4-d]pyrimidin-2- (m, 2H), 3.99 (s, 3H), 3.94-3.85 (m, 2H),amine  

3.71 (q, J = 8.5 Hz, 2H), 3.63 (s, 3H), 2.45 (s, 3H), 2.43 (s, 3H),2.05-1.97 (m, 4H). HRMS (ESI) MS m/z calcd for C₂₇H₃₃N₇O₂ [M + 2H]/2⁺243.6342, found 243.6348. Using 2-oxa-7-azaspiro[4.4]nonane for 60hours. PM B. 34 1-(2-((4-(1,2-dimethyl-1H- ¹H NMR (500 MHz, MeOH-d₄): δppm 0.003 imidazol-5-yl)-2- 9.11 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H),methoxyphenyl)amino)-6- 7.09-7.07 (m, 2H), 7.04 (d, J = 0.5 Hz,methylpyrido[3,4- 1H), 6.91 (s, 1H), 4.20-4.41 (m, 2H),d]pyrimidin-8-yl)piperidine- 4.02 (s, 3H), 3.64 (s, 3H), 3.64-3.60 (m,4-carbonitrile  

2H), 3.08 (m, 1H), 2.50 (s, 3H), 2.45 (s, 3H), 2.21-2.15 (m, 2H),2.09-2.04 (m, 2H). HRMS (ESI) MS m/z calcd for C₂₆H₂₉N₈O [M + H]⁺470.2487, found 470.2468. Using piperidine-4-carbonitrile for 60 hours.PM B. 35 1-(2-((4-(1,2-dimethyl-1H- ¹H NMR (500 MHz, MeOH-d₄): δ ppm0.002 imidazol-5-yl)-2- 9.06 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H),methoxyphenyl)amino)-6- 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 7.08 (d, J =methylpyrido[3,4- 2.0 Hz, 1H), 6.91 (s, 1H), 6.88 (s, 1H),d]pyrimidin-8-yl)-3- 4.72 (d, J = 9.0 Hz, 2H), 4.35 (d, J = 9.0methylazetidine-3- Hz, 2H), 3.99 (s, 3H), 3.64 (s, 3H), 2.45carbonitrile  

(br s, 6H), 1.72 (s, 3H). HRMS (ESI) MS m/z calcd for C₂₅H₂₈N₈O [M +2H]/2⁺ 228.6201, found 228.6192. Using 3-methylazetidine-3-carbonitrilehydrochloride for 60 hours. PM B. 36 N-(2-ethoxy-4-(4-methyl- ¹H NMR(500 MHz, MeOH-d₄): δ ppm 0.002 4H-1,2,4-triazol-3- 9.07 (s, 1H), 8.57(app t, J = 4.0 Hz, 2H), yl)phenyl)-6-methyl-8-(1- 7.44 (dd, J = 8.5,2.0 Hz, 1H), 7.39 (d, J = oxa-6- 2.0 Hz, 1H), 6.83 (s, 1H), 4.71 (br d,J = azaspiro[3.3]heptan-6- 11.0 Hz, 2H), 4.60-4.57 (m, 4H), 4.29yl)pyrido[3,4-d]pyrimidin-2- (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 2.96 (t,amine  

J = 7.5 Hz, 2H), 2.45 (s, 3H), 1.55 (t, J = 7.0 Hz, 3H). HRMS (ESI) MSm/z calcd for C₂₄H₂₇N₈O₂ [M + H]⁺ 459.2251, found 459.2226. Using1-oxa-6-azaspiro[3.3]heptane oxalate. 37 1-(2-((2-ethoxy-4-(4- ¹H NMR(500 MHz, MeOH-d₄): δ ppm 0.003 methyl-4H-1,2,4-triazol-3- 9.02 (s, 1H),8.55 (s, 1H), 8.53 (d, J = 8.0 yl)phenyl)amino)-6- Hz, 1H), 7.37 (d, J =2.0 Hz, 1H), 7.35 methylpyrido[3,4- (dd, J = 8.0, 2.0 Hz, 1H), 6.73 (s,1H), d]pyrimidin-8-yl)-3- 4.29 (q, J = 7.0 Hz, 2H), 4.19-4.13 (m,methylpyrrolidin-3-ol  

2H), 4.09-4.00 (m, 2H), 3.87 (s, 3H), 2.44 (s, 3H), 2.06-1.97 (m, 2H),1.54 (t, J = 7.0 Hz, 3H), 1.48 (s, 3H). HRMS (ESI) MS m/z calcd forC₂₄H₂₉N₈O₂ [M + H]⁺ 461.2408, found 461.2393. Using3-methylpyrrolidin-3-ol hydrochloride at 120° C. for 18 hours. PM C. 381-(2-((2-ethoxy-4-(4- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.003methyl-4H-1,2,4-triazol-3- 9.07 (s, 1H), 8.55 (s, 1H), 8.46 (d, J = 8.0yl)phenyl)amino)-6- Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.39methylpyrido[3,4- (dd, J = 8.0, 2.0 Hz, 1H), 6.84 (s, 1H),d]pyrimidin-8- 4.38 (d, J = 7.0 Hz, 2H), 4.29 (q, J = 7.0yl)pyrrolidine-3-carbonitrile  

Hz, 2H), 4.15 (m, 1H), 4.01 (m, 1H), 3.87 (s, 3H), 3.44 (m, 1H), 2.46(s, 3H), 2.42 (m, 1H), 2.29 (m, 1H), 1.54 (t, J = 7.0 Hz, 3H). HRMS(ESI) MS m/z calcd for C₂₄H₂₇N₉O [M + 2H]/2⁺ 228.6164, found 228.6162.Using pyrrolidine-3-carbonitrile hydrochloride for 60 hours. PM E. 39N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.0034H-1,2,4-triazol-3- 9.04 (s, 1H), 8.55 (s, 1H), 8.50 (d, J = 8.5yl)phenyl)-8-(3- Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.36methoxypyrrolidin-1-yl)-6- (dd, J = 8.5, 2.0 Hz, 1H), 6.76 (s, 1H),methylpyrido[3,4- 4.29 (d, J = 7.0 Hz, 2H), 4.14 (q, J = 7.0d]pyrimidin-2-amine  

Hz, 2H), 4.09-4.04 (m, 2H), 4.01 (m, 1H), 3.87 (s, 3H), 3.38 (s, 3H),2.44 (s, 3H), 2.16 (m, 1H), 2.09 (m, 1H), 1.54 (t, J = 7.0 Hz, 3H). HRMS(ESI) MS m/z calcd for C₂₄H₂₉N₈O₂ [M + H]⁺ 462.2436, found 462.2413.Using 3-methoxypyrrolidine hydrochloride. PM F. 40N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.0054H-1,2,4-triazol-3- 9.08 (s, 1H), 8.55 (s, 1H), 8.45 (d, J = 8.5yl)phenyl)-6-methyl-8-(3- Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.32(trifluoromethyl)azetidin-1- (dd, J = 8.5, 2.0 Hz, 1H), 6.85 (s, 1H),yl)pyrido[3,4-d]pyrimidin-2- 4.66 (app t, J = 9.5 Hz, 2H), 4.50 (dd,amine  

J = 9.5, 5.5 Hz, 2H), 4.28 (d, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.59 (m,1H), 2.46 (d, J = 0.5 Hz, 3H), 1.53 (t, J = 7.0 Hz, 3H). HRMS (ESI) MSm/z calcd for C₂₃H₂₄F₃N₈O [M + H]⁺ 485.202, found 485.2022. Using3-(trifluoromethyl)azetidine. PM A. 41 1-(2-((2-ethoxy-4-(4- ¹H NMR (500MHz, MeOH-d₄): δ ppm 0.004 methyl-4H-1,2,4-triazol-3- 9.04 (s, 1H), 8.55(s, 1H), 8.54 (d, J = 8.5 yl)phenyl)amino)-6- Hz, 1H), 7.37 (d, J = 1.5Hz, 1H), 7.34 methylpyrido[3,4- (dd, J = 8.5, 1.5 Hz, 1H), 6.77 (s, 1H),d]pyrimidin-8-yl)-3- 4.44 (br d, J = 9.5 Hz, 2H), 4.29 (br d,ethylazetidin-3-ol  

J = 9.5 Hz, 2H), 4.28 (d, J = 7.0 Hz, 2H), 3.86 (s, 3H), 2.44 (s, 3H),1.86 (q, J = 7.5 Hz, 2H), 1.54 (t, J = 7.0 Hz, 3H), 1.04 (t, J = 7.5 Hz,3H). HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₈O₂ [M + 2H]/2⁺ 231.6254, found231.6243. Using 3-ethyl-3-hydroxy azetidine. PM A. 428-(2,2-dimethylazetidin-1- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.010yl)-N-(2-ethoxy-4-(4- 8.98 (s, 1H), 8.54 (s, 1H), 8.52 (d, J = 8.0methyl-4H-1,2,4-triazol-3- Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.33yl)phenyl)-6- (dd, J = 8.0, 2.0 Hz, 1H), 6.65 (s, 1H), methylpyrido[3,4-4.70-4.66 (m, 2H), 4.27 (d, J = 7.0 Hz, d]pyrimidin-2-amine  

2H), 3.85 (s, 3H), 2.39 (s, 3H), 2.22 (dd, J = 9.0, 7.5 Hz, 2H), 1.71(s, 6H), 1.54 (t, J = 7.0 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₈O[M + H]⁺ 445.2459, found 445.2461. Using 2,2-dimethylazetidine. PM F. 431-(2-((2-ethoxy-4-(4- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.003methyl-4H-1,2,4-triazol-3- 9.07 (s, 1H), 8.55 (s, 1H), 8.45 (d, J = 8.0yl)phenyl)amino)-6- Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.37methylpyrido[3,4- (dd, J = 8.0, 2.0 Hz, 1H), 6.84 (s, 1H),d]pyrimidin-8-yl)-3- 4.61 (d, J = 12.0 Hz, 1H), 4.28 (d, J = 7.0methylpyrrolidine-3- Hz, 2H), 4.18 (m, 1H), 4.11 (m, 1H), 4.01carbonitrile  

(d, J = 12.0 Hz, 1H), 3.87 (s, 3H), 2.45 (s, 3H), 2.47 (m, 1H), 2.12 (m,1H), 1.56 (s, 3H), 1.54 (t, J = 7.0 Hz, 3H). HRMS (ESI) MS m/z calcd forC₂₅H₂₉N₉O [M + 2H]/2⁺ 235.6242, found 235.6243. Using 3-cyano-3-methylpyrrolidine hydrochloride. PM F. 44 N-(2-ethoxy-4-(4-methyl- ¹H NMR (500MHz, MeOH-d₄): δ ppm 0.002 4H-1,2,4-triazol-3- 9.04 (s, 1H), 8.56 (d, J= 8.0 Hz, 1H), yl)phenyl)-6-methyl-8-(2- 8.55 (s, 1H), 7.37 (d, J = 2.0Hz, 1H), azaspiro[3.4]octan-2- 7.32 (dd, J = 8.5, 2.0 Hz, 1H), 6.76 (s,yl)pyrido[3,4-d]pyrimidin-2- 1H), 4.35 (br s, 4H), 4.28 (d, J = 7.0 Hz,amine  

2H), 3.86 (s, 3H), 2.44 (s, 3H), 1.92-1.89 (m, 4H), 1.71-1.68 (m, 4H),1.54 (t, J = 7.0 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₆H₃₂N₈O [M +2H]/2⁺ 235.1344, found 235.1336. Using 2-azaspiro[3.4]octane. PM F. 458-(3,3-difluoroazetidin-1- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.006yl)-N-(2-ethoxy-4-(4- 9.24 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H),methyl-4H-1,2,4-triazol-3- 8.15 (d, J = 8.8 Hz, 1H), 7.44-7.33 (m,yl)phenyl)-6- 2H), 7.02 (m, 1H), 4.68 (t, J = 12.6 Hz, methylpyrido[3,4-4H), 4.25-4.15 (m, 2H), 3.79 (s, 3H), d]pyrimidin-2-amine  

2.43 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H). HRMS (ESI) MS m/z calcd forC₂₂H₂₄F₂N₈O [M + 2H]/2⁺ 227.1015, found 227.1021. Using3,3-difluoroazetidine hydrochloride at 130° C. PM F. 46N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.0034H-1,2,4-triazol-3- 9.24 (d, J = 1.5 Hz, 1H), 8.62-8.49 (m,yl)phenyl)-8-(4- 2H), 8.45 (s, 1H), 7.41 (s, 1H), 7.36 (d, J =methoxypiperidin-1-yl)-6- 8.5 Hz, 1H), 7.05 (s, 1H), 4.37-4.10 (m,methylpyrido[3,4- 4H), 3.79 (s, 3H), 3.45 (m, 1H), 3.34 (s,d]pyrimidin-2-amine  

2H), 3.30 (s, 3H), 2.43 (s, 3H), 2.10-1.97 (m, 2H), 1.70-1.57 (m, 2H),1.43 (t, J = 6.9 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₅H₃₁N₈O₂ [M +H]⁺ 475.2564, found 475.2540. Using 4-methoxypiperidine hydrochloride at130° C. PM F. 47 Racemic-N-(2-ethoxy-4-(4- ¹H NMR (500 MHz, DMSO-d₆): δppm 0.006 methyl-4H-1,2,4-triazol-3- 9.24 (s, 1H), 8.60-8.51 (m, 2H),8.43 (s, yl)phenyl)-8-(3- 1H), 7.44-7.34 (m, 2H), 7.04 (d, J = 1.0methoxypiperidin-1-yl)-6- Hz, 1H), 4.43 (d, J = 10.9 Hz, 1H), 4.30methylpyrido[3,4- (d, J = 13.1 Hz, 1H), 4.24 (q, J = 6.9 Hz,d]pyrimidin-2-amine  

2H), 3.79 (s, 3H), 3.45 (m, 1H), 3.28 (m, 1H), 3.22 (s, 3H), 3.14 (dd, J= 12.4, 8.5 Hz, 1H), 2.43 (s, 3H), 2.09 (m, 1H), 1.87 (m, 1H), 1.66 (m,1H), 1.50-1.35 (m, 4H). HRMS (ESI) MS m/z calcd for C₂₅H₃₁N₈O₂ [M + H]⁺475.2564, found 475.2547. Using racemic-3-methoxpiperidine hydrochlorideat 130° C. PM F. 48 Racemic-N-(2-ethoxy-4-(4- ¹H NMR (500 MHz, DMSO-d₆):δ ppm 0.003 methyl-4H-1,2,4-triazol-3- 9.26 (s, 1H), 8.57 (s, 1H), 8.49(s, 1H), yl)phenyl)-6-methyl-8-(2- 8.47 (d, J = 8.3 Hz, 1H), 7.42 (d, J= 1.9 methylmorpholino)pyrido Hz, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H),[3,4-d]pyrimidin-2-amine  

7.09 (s, 1H), 4.60 (d, J = 12.5 Hz, 1H), 4.50 (d, J = 12.9 Hz, 1H), 4.24(q, J = 7.0 Hz, 2H), 3.95 (d, J = 13.0 Hz, 1H), 3.87- 3.71 (m, 5H), 2.95(td, J = 12.2, 3.1 Hz, 1H), 2.62 (dd, J = 12.6, 10.2 Hz, 1H), 2.44 (s,3H), 1.42 (t, J = 6.9 Hz, 3H), 1.13 (d, J = 6.2 Hz, 3H). HRMS (ESI) MSm/z calcd for C₂₄H₂₉N₈O₂ [M + H]⁺ 461.2408, found 461.2390. Usingracemic-2-methylmorpholine hydrochloride at 130° C. PM B. 49N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.0034H-1,2,4-triazol-3- 9.23 (d, J = 3.1 Hz, 1H), 8.62-8.51 (m,yl)phenyl)-8-(4-methoxy-4- 2H), 8.43 (d, J = 3.7 Hz, 1H), 7.40 (s,methylpiperidin-1-yl)-6- 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.03 (s,methylpyrido[3,4- 1H), 4.24 (q, J = 6.9 Hz, 2H), 4.17 (d,d]pyrimidin-2-amine  

J = 12.3 Hz, 2H), 3.79 (s, 3H), 3.44-3.36 (m, 2H), 3.16 (s, 3H), 2.43(s, 3H), 1.85 (d, J = 13.6 Hz, 2H), 1.76-1.65 (m, 2H), 1.43 (t, J = 6.9Hz, 3H), 1.19 (s, 3H). HRMS (ESI) MS m/z calcd for C₂₆H₃₄N₈O₂ [M +2H]/2⁺ 245.1397, found 245.1397. Using 4-methoxy-4-methylpiperidine at130° C. PM F. 50 8-(3- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.002azabicyclo[3.1.0]hexan-3- 9.13 (d, J = 1.0 Hz, 1H), 8.57 (s, 1H),yl)-N-(2-ethoxy-4-(4- 8.44 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H),methyl-4H-1,2,4-triazol-3- 7.39 (s, 1H), 7.37 (dd, J = 8.1, 1.8 Hz,yl)phenyl)-6- 1H), 6.80 (s, 1H), 4.41 (d, J = 11.6 Hz, methylpyrido[3,4-2H), 4.21 (q, J = 6.9 Hz, 2H), 3.80 (s, d]pyrimidin-2-amine  

3H), 3.69 (d, J = 11.4 Hz, 2H), 2.36 (s, 3H), 1.68-1.60 (m, 2H), 1.39(t, J = 6.9 Hz, 3H), 0.68 (td, J = 7.6, 4.3 Hz, 1H), 0.19 (q, J = 4.1Hz, 1H). HRMS (ESI) MS m/z calcd for C₂₄H₂₇N₈O [M + H]⁺ 443.2302, found443.2281. Using 3-azabicyclo[3.1.0]hexane hydrochloride at 130° C. PM F.51 8-(3- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.006(dimethylamino)azetidin-1- 9.16 (d, J = 1.2 Hz, 1H), 8.56 (s, 1H),yl)-N-(2-ethoxy-4-(4- 8.43 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H),methyl-4H-1,2,4-triazol-3- 7.39 (d, J = 1.9 Hz, 1H), 7.35 (dd, J =yl)phenyl)-6- 8.3, 1.8 Hz, 1H), 6.82 (s, 1H), 4.38 (br s,methylpyrido[3,4- 2H), 4.21 (q, J = 7.0 Hz, 2H), 4.12 (br s,d]pyrimidin-2-amine  

2H), 3.78 (s, 3H), 3.15 (br s, 1H), 2.37 (s, 3H), 2.12 (s, 6H), 1.40 (t,J = 6.9 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₉O [M + H]⁺460.2568, found 460.2545. Using N,N-dimethylazetidin-3-aminedihydrochloride at 130° C. PM F. 52 1-(2-(2-ethoxy-4-(4- ¹H NMR (500MHz, DMSO-d₆): δ ppm 0.002 methyl-4H-1,2,4-triazol-3- 9.24 (s, 1H), 8.61(d, J = 8.4 Hz, 1H), yl)phenylamino)-6- 8.57 (s, 1H), 8.42 (s, 1H), 7.40(s, 1H), methylpyrido[3,4- 7.37 (dd, J = 8.4, 1.9 Hz, 1H), 7.03 (s,d]pyrimidin-8-yl)piperidin- 1H), 4.74 (d, J = 4.4 Hz, 1H), 4.37 (d, 4-ol 

J = 12.1 Hz, 2H), 4.24 (q, J =6.9 Hz, 2H), 3.79 (s, 3H), 3.71 (m, 1H),3.26-3.14 (m, 2H), 2.42 (s, 3H), 1.97-1.88 (m, 2H), 1.68-1.55 (m, 2H),1.43 (t, J = 6.9 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₈O₂ [M +H]⁺ 461.2408, found 461.2390. Using piperidin-4-ol hydrochloride at 130°C. PM F. 53 (R)-N8-(3,3- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.005dimethylbutan-2-yl)-N2-(2- 9.15 (s, 1H), 8.57 (s, 1H), 8.43 (d, J = 8.3ethoxy-4-(4-methyl-4H- Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.311,2,4-triazol-3-yl)phenyl)- (dd, J = 8.2, 1.9 Hz, 1H), 6.72 (d, J = 1.06-methylpyrido[3,4- Hz, 1H), 6.43 (d, J = 9.5 Hz, 1H), 4.23d]pyrimidine-2,8-diamine  

(q, J = 6.9 Hz, 2H), 4.13 (dq, J = 9.4, 6.6 Hz, 1H), 3.78 (s, 3H), 2.38(s, 3H), 1.41 (t, J = 6.9 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 1.00 (s,9H). HRMS (ESI) MS m/z calcd for C₂₅H₃₃N₈O [M + H]⁺ 461.2777, found461.2772. Using (R)-3,3-dimethylbutan-2-amine at 130° C. for 48 hours.PM F. 54 (S)-N8-(3,3-dimethylbutan- ¹H NMR (500 MHz, DMSO-d₆): δ ppm0.004 2-yl)-N2-(2-ethoxy-4-(4- 9.15 (s, 1H), 8.57 (s, 1H), 8.43 (d, J =8.3 methyl-4H-1,2,4-triazol-3- Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.31yl)phenyl)-6- (dd, J = 8.2, 1.9 Hz, 1H), 6.72 (d, J = 1.0methylpyrido[3,4- Hz, 1H), 6.43 (d, J = 9.5 Hz, 1H), 4.23d]pyrimidine-2,8-diamine  

(q, J = 6.9 Hz, 2H), 4.13 (dq, J = 9.4, 6.6 Hz, 1H), 3.78 (s, 3H), 2.38(s, 3H), 1.41 (t, J = 6.9 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 1.00 (s,9H). HRMS (ESI) MS m/z calcd for C₂₅H₃₃N₈O [M + H]⁺ 461.2777, found461.2777. Using (S)-3,3-dimethylbutan-2-amine at 130° C. for 48 hours.PM F. 55 N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.0044H-1,2,4-triazol-3- 9.15 (s, 1H), 8.58 (s, 1H), 8.39 (s, 1H),yl)phenyl)-6-methyl-8-(2- 8.32 (d, J = 8.1 Hz, 1H), 7.44-7.33 (m,azaspiro[3.3]heptan-2- 2H), 6.80 (s, 1H), 4.31 (br s, 4H), 4.22yl)pyrido[3,4-d]pyrimidin-2- (q, J = 6.9 Hz, 2H), 3.80 (s, 3H), 2.37 (s,amine  

3H), 2.19 (t, J = 7.6 Hz, 4H), 1.88-1.73 (m, 2H), 1.42 (t, J = 6.9 Hz,3H). HRMS (ESI) MS m/z calcd for C₂₅H₂₉N₈O [M + H]⁺ 457.2464, found457.2473. Using 2-azaspiro[3.3]heptane hydrochloride at 130° C. PM F. 56N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.0064H-1,2,4-triazol-3- 9.13 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H),yl)phenyl)-6-methyl-8- 8.23 (d, J = 8.2 Hz, 1H), 7.39-7.29 (m,(pyrrolidin-1-yl)pyrido[3,4- 2H), 6.76 (d, J = 0.8 Hz, 1H), 4.21 (q, J =d]pyrimidin-2-amine  

6.9 Hz, 2H), 3.88 (s, 4H), 3.78 (s, 3H), 2.37 (s, 3H), 1.94-1.83 (m,4H), 1.41 (t, J = 6.9 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₃H₂₇N₈O[M + H]⁺ 431.2308, found 431.2315. Using pyrrolidine at 130° C. for 24hours. PM F. 57 N2-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, DMSO-d₆): δppm 0.003 4H-1,2,4-triazol-3- 9.15 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H),yl)phenyl)-6-methyl-N8- 8.32 (d, J = 8.1 Hz, 1H), 7.45-7.29 (m,(oxetan-3- 2H), 6.79 (s, 1H), 4.77 (t, J = 5.3 Hz, 1H),ylmethyl)pyrido[3,4- 4.38 (br s, 2H), 4.22 (q, J = 6.9 Hz, 2H),d]pyrimidine-2,8-diamine  

4.11 (br s, 2H), 3.78 (s, 3H), 3.59 (t, J = 5.9 Hz, 2H), 2.81 (m, 1H),2.37 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H). HRMS (ESI) MS m/z calcd forC₂₃H₂₇N₈O₂ [M + H]⁺ 447.2257, found 447.2260. Usingoxetan-3-ylmethanamine at 130° C. for 24 hours. PM F. 58N2-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.5184H-1,2,4-triazol-3- 8.93 (m, 1H), 8.84 (d, J = 7.0 Hz, 1H),yl)phenyl)-6-methyl-N8-(1- 8.55 (s, 1H), 7.37-7.34 (m, 2H), 6.17 (s,methylazetidin-3- 1H), 4.29 (q, J = 7.0 Hz, 2H), 4.13 (m,yl)pyrido[3,4-d]pyrimidine- 1H), 3.86 (d, J = 2.0 Hz, 3H), 2.91-2.792,8-diamine  

(m, 4H), 2.44 (d, J = 1.0 Hz, 3H), 2.34 (s, 3H), 1.55 (t, J = 7.0 Hz,3H). HRMS (ESI) MS m/z calcd for C₂₃H₂₈N₉O [M + H]⁺ 446.2417, found446.2421. Using 1-methylazetidin-3-amine. PM D. 59N2-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz, MeOH-d₄): δ ppm 0.0044H-1,2,4-triazol-3- 9.04 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H),yl)phenyl)-N8-((1- 8.55 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H),methoxycyclobutyl)methyl)- 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 6.74 (s,6-methylpyrido[3,4- 1H), 4.30 (d, J = 7.0 Hz, 2H), 3.87 (s,d]pyrimidine-2,8-diamine  

3H), 3.86 (s, 2H), 3.34 (s, 3H), 2.46 (s, 3H), 2.30-2.23 (m, 2H),2.06-2.01 (m, 2H), 1.84 (m, 1H), 1.77 (m, 1H), 1.56 (t, J = 7.0 Hz, 3H).HRMS (ESI) MS m/z calcd for C₂₅H₃₁N₈O₂ [M + H]⁺ 475.2570, found475.2571. Using (1- methoxycyclobutyl)methanamine hydrochloride at 120°C. for 4 days. PM E. 60 N-(2-ethoxy-4-(4-methyl- ¹H NMR (500 MHz,DMSO-d₆): δ ppm 0.003 4H-1,2,4-triazol-3- 9.15 (s, 1H), 8.55 (s, 1H),8.43 (s, 1H), yl)phenyl)-8-(3-ethyl-3- 8.25 (d, J = 8.3 Hz, 1H), 7.38(d, J = 1.8 methoxyazetidin-1-yl)-6- Hz, 1H), 7.32 (dd, J = 8.3, 1.8 Hz,1H), methylpyrido[3,4- 6.82 (d, J = 1.0 Hz, 1H), 4.27-4.03 (m,d]pyrimidin-2-amine  

6H), 3.77 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H), 1.82 (q, J = 7.3 Hz, 2H),1.39 (t, J = 6.9 Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H). HRMS (ESI) MS m/zcalcd for C₂₅H₃₁N₈O₂ [M + H]⁺ 475.2570, found 475.2567. Using3-ethyl-3-methoxyazetidine hydrochloride (Preparation 66) at 130° C. for18 hours. PM G. 61 8-(3-ethoxy-3- ¹H NMR (500 MHz, DMSO-d₆): δ ppm 0.004methylazetidin-1-yl)-N-(2- 9.15 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H),ethoxy-4-(4-methyl-4H- 8.23 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 1.81,2,4-triazol-3-yl)phenyl)- Hz, 1H), 7.34 (dd, J = 8.3, 1.8 Hz, 1H),6-methylpyrido[3,4- 6.82 (s, 1H), 4.34-4.09 (m, 6H), 3.78 (s,d]pyrimidin-2-amine  

3H), 3.43 (q, J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.47 (s, 3H), 1.39 (t, J =6.9 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H). HRMS (ESI) MS m/z calcd forC₂₅H₃₁N₈O₂ [M + H]⁺ 475.2570, found 475.2575. Using3-ethoxy-3-methylazetidine hydrochloride (Preparation 67) at 130° C. for18 hours. PM F. 62 N-(2-(difluoromethoxy)-4- ¹H NMR (500 MHz, CDCl₃): δppm 8.98 0.016 (4-methyl-4H-1,2,4-triazol- (s, 1H), 8.77 (d, J = 8.5 Hz,1H), 8.24 (s, 3-yl)phenyl)-8-(3,3- 1H), 7.74 (s, 1H), 7.64-7.55 (m, 2H),dimethylazetidin-1-yl)-6- 6.71 (t, J = 72.9 Hz, 1H), 6.67 (s, 1H),methylpyrido[3,4- 4.24 (s, 4H), 3.84 (s, 3H), 2.50 (s, 3H),d]pyrimidin-2-amine  

1.39 (s, 6H). HRMS (ESI) MS m/z calcd for C₂₃H₂₅F₂N₈O [M + H]⁺ 467.2119,found 467.2117. Using 3,3-dimethylazetidine hydrochloride at 130° C. for60 hours. PM G.

Preparation 18-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

To a solution ofN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 32, 1.88 g, 7.63 mmol) in THF (70 mL) was added sodiumhydride (60% w/w, 500 mg, 12.50 mmol) at 0° C. The reaction was stirredat room temperature for 30 minutes before cooling to 0° C.8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation24, 2.50 g, 9.70 mmol) was added and the reaction was stirred whilstwarming to room temperature for 18 hours. A solution of aqueous 2M NaOHand MeOH were added (25 mL each) and the resulting mixture stirred atroom temperature for 1 hour before concentrating in vacuo. The residuewas partitioned between DCM and water. The aqueous layer was extractedwith DCM and the combined organic layers were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0-6% MeOH in DCM to afford the titlecompound (3.24 g, quant).

¹H NMR (500 MHz, DMSO-d₆): δ ppm 9.46 (s, 1H), 8.85 (d, J=8.3 Hz, 1H),8.79 (s, 1H), 8.56 (s, 1H), 7.74 (d, J=1.0 Hz, 1H), 7.49-7.36 (m, 2H),4.25 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 2.58 (s, 3H), 1.43 (t, J=6.9 Hz,3H).

HRMS (ESI) MS m/z calcd for C₁₉H₁₉ClN₇O [M+H]⁺ 396.1339, found 396.1335.

Preparation 28-chloro-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

To a solution ofN-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide(Preparation 37, 280 mg, 1.087 mmol) in THF (10 mL) was added sodiumhydride (71 mg, 1.782 mmol) at 0° C. and the reaction was stirred atroom temperature for 30 minutes before cooling to 0° C.8-chloro-6-methyl-2-(methysulfonyl)pyrido[3,4-d]pyrimidine (Preparation24, 333 mg, 1.087 mmol) was added and the reaction was stirred at roomtemperature for 18 hours. Aqueous NaOH (2M) and MeOH were added (25 mLeach) and the resulting mixture stirred at room temperature for 1 hourbefore concentrating in vacuo. The residue was partitioned between DCMand water. The aqueous layer was extracted with DCM and the combinedorganic layers were dried (MgSO₄) and concentrated in vacuo. The residuewas purified by reverse phase column chromatography eluting with waterand MeOH to afford the title compound (230 mg, 54%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.29 (s, 1H), 9.09 (d, J=8.0 Hz, 1H),7.62 (d, J=0.5 Hz, 1H), 7.12 (dd, J=8.0, 2.0 Hz, 1H), 7.09 (d, J=2.0 Hz,1H), 6.91 (s, 1H), 4.04 (s, 3H), 3.64 (s, 3H), 2.63 (s, 3H), 2.45 (s,3H).

HRMS (ESI) MS m/z calcd for C₂₀H₂₀N₆ClO [M+H]⁺ 396.141, found 396.1389.

Preparation 38-chloro-N-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

A solution ofN-(2-(difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 38, 102 mg, 0.380 mmol) in THF (3.5 mL) was treated withsodium hydride (60% w/w, 25 mg, 0.625 mmol) at 0° C. The reaction wasstirred at room temperature for 30 min before cooling to 0° C.8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation24, 122 mg, 0.473 mmol) was added and the reaction stirred at roomtemperature for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH (0.5 mL)were added and the resulting mixture stirred at room temperature for 2hours before concentrating in vacuo. The residue was partitioned betweenDCM and water. The aqueous layer was extracted with DCM and the combinedorganics were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 0-7% MeOH inEtOAc to afford the title compound (30 mg, 19%).

¹H NMR (500 MHz, CDCl₃): δ ppm 9.37 (d, J=8.6 Hz, 1H), 9.19 (s, 1H),8.24 (s, 1H), 8.19 (s, 1H), 7.71 (m, 1H), 7.63 (dd, J=8.6, 2.0 Hz, 1H),7.43 (d, J=0.9 Hz, 1H), 6.76 (t, J=72.7 Hz, 1H), 3.87 (s, 3H), 2.71 (d,J=0.8 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₈H₁₅ClF₂N70 [M+H]⁺ 418.0995, found418.0990.

Preparation 46-methyl-2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine

To a cooled (0° C.) solution of6-methyl-2-(methylthio)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 14, 133 mg, 0.481 mmol) in DCM (30 mL) was added mCPBA (77%w/w, 259 mg, 1.155 mmol). The reaction mixture was stirred for 18 hourswhilst warming slowly to room temperature. Further mCPBA (30 mg) wasadded and the reaction continued for 2 hours. The reaction was dilutedwith DCM and saturated aqueous NaHCO₃ solution. The organic layer wascollected, washed with brine, dried (MgSO₄) and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 0-10% MeOH in DCM to afford the title compound (140 mg, 94%).

¹H NMR (500 MHz, Acetone-d₆): δ ppm 9.45 (s, 1H), 7.41 (br s, 1H), 6.95(s, 1H), 3.59 (d, J=6.0 Hz, 2H), 3.44 (s, 3H), 2.51 (d, J=0.5 Hz, 3H),1.03 (s, 9H).

HRMS (ESI) MS m/z calcd for C₁₄H₂₁N₄O₂S [M+H]⁺ 309.138, found 309.1364.

The following Preparations were prepared according to the methoddescribed for Preparation 4 using the appropriatemethylthiopyridopyrimidine as described below:

Preparation No Name/Structure Data 5

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.41 (s, 1H), 6.93 (s, 1H), 4.00 (td, J= 8.5, 6.0 Hz, 1H), 3.91 (td, J = 8.5, 6.0 Hz, 1H), 3.84 (d, J = 8.5 Hz,1H), 3.83 (d, J = 13.5 Hz, 1H), 3.68 (d, J = 13.5 Hz, 1H), 3.47 (d, J =8.5 Hz, 1H), 3.46 (s, 3H), 2.53 (d, J = 0.5 Hz, 3H), 2.06 (m, 1H), 1.73(m, 1H), 1.23 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₅H₂₁N₄O₃S [M + H]⁺337.1329, found 337.1319. Using 6-methyl-N-((3-methyltetrahydrofuran-3-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- amine (Preparation 15). 6

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.43 (s, 1H), 6.97 (d, J = 0.5 Hz, 1H),3.84 (s, 2H), 3.46 (s, 3H), 2.53 (d, J = 0.5 Hz, 3H), 2.22-2.17 (m, 2H),2.13-2.06 (m, 2H), 1.79 (m, 1H), 1.67 (m, 1H). HRMS (ESI) MS m/z calcdfor C₁₄H₁₉N₄O₃S [M + H]⁺ 323.1172, found 323.1158. Using1-(((6-methyl-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclobutanol (Preparation 16). 7

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.46 (s, 1H), 7.08 (s, 1H), 4.54 (br s,2H), 3.44 (s, 3H), 2.56 (s, 3H), 1.80 (s, 3H). HRMS (ESI) MS m/z calcdfor C₁₄H₁₆N₅O₂S [M + H]⁺ 318.1019, found 318.1009. Using3-methyl-1-(6-methyl-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)azetidine-3-carbonitrile (Preparation 17). 8

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.38 (s, 1H), 6.94 (s, 1H), 4.29 (br s,4H), 3.73 (app t, J = 5.5 Hz, 4H), 3.43 (s, 3H), 2.53 (s, 3H), 1.92 (appt, J = 5.5 Hz, 4H). HRMS (ESI) MS m/z calcd for C₁₆H₂₁N₄O₃S [M + H]⁺349.1329, found 349.1318. Using 2-(6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-7- oxa-2-azaspiro[3.5]nonane(Preparation 18). 9

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.48 (s, 1H), 7.15 (s, 1H), 4.55-4.51(m, 2H), 3.97-3.92 (m, 2H), 3.43 (s, 3H), 3.15 (m, 1H), 2.57 (s, 3H),2.19-2.13 (m, 2H), 2.04-1.98 (m, 2H). HRMS (ESI) MS m/z calcd forC₁₅H₁₈N₅O₂S [M + H]⁺ 332.1176, found 332.1164. Using 1-(6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)piperidine-4-carbonitrile(Preparation 19). 10

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.39 (s, 1H), 6.95 (s, 1H), 5.30 (br s,2H), 4.43 (br s, 2H), 3.41 (s, 3H), 2.53 (s, 3H), 1.60 (s, 3H). HRMS(ESI) MS m/z calcd for C₁₃H₁₇N₄O₃S [M + H]⁺ 309.1016, found 309.1006.Using 3-methyl-1-(6-methyl-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)azetidin-3-ol (Preparation 20). 11

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.42 (s, 1H), 6.95 (s, 1H), 4.77 (d, J= 6.0 Hz, 2H), 4.41 (d, J = 6.0 Hz, 2H), 3.89 (s, 2H), 3.46 (s, 3H),2.53 (s, 3H), 1.43 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₄H₁₉N₄O₃S [M +H]⁺ 323.1172, found 323.1165. Using 6-methyl-N-((3-methyloxetan-3-yl)methyl)-2-(methylthio)pyrido[3,4- d]pyrimidin-8-amine (Preparation21). 12

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.39 (s, 1H), 6.92 (s, 1H), 4.44 (m,1H), 4.07-4.03 (m, 2H), 3.62 (td, J = 12.0, 2.0 Hz, 2H), 3.45 (s, 3H),2.54 (s, 3H), 2.10- 2.06 (m, 2H), 1.82-1.74 (m, 2H). HRMS (ESI) MS m/zcalcd for C₁₄H₁₉N₄O₃S [M + H]⁺ 323.1172, found 323.1158. Using6-methyl-2-(methylthio)-N- (tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 22). 13

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.37 (s, 1H), 6.91 (s, 1H), 4.53-4.09(br m, 4H), 3.41 (s, 3H), 2.52 (s, 3H), 1.41 (s, 6H). HRMS (ESI) MS m/zcalcd C₁₄H₁₉N₄SO₂ [M + H]⁺ 307.1229, found 307.1225. Using8-(3,3-dimethylazetidin-1-yl)-6- methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 23).

Preparation 146-methyl-2-(methylthio)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine

To a solution of 8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine(Preparation 25, 500 mg, 2.215 mmol) in NMP (20 mL) was addedneopentylamine (0.52 mL, 4.43 mmol) and triethylamine (1.56 mL, 11.08mmol). The reaction mixture was heated to 100° C. for 36 hours. Thereaction mixture was diluted with EtOAc and water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0-50% EtOAc in cyclohexane to afford thetitle compound (548 mg, 89%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.02 (s, 1H), 6.71 (d, J=0.5 Hz, 1H),3.47 (s, 2H), 2.66 (s, 3H), 2.44 (d, J=0.5 Hz, 3H), 1.05 (s, 9H).

HRMS (ESI) MS m/z calcd for C₁₄H₂₁N₄S [M+H]⁺ 277.1481, found 277.1467.

The following Preparations were prepared according to the methoddescribed for Preparation 14 using8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine (Preparation 25)and the appropriate amine as described below:

Preparation No Name/Structure Data 15

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.00 (s, 1H), 6.73 (d, J = 0.5 Hz, 1H),4.02 (td, J = 8.5, 6.5 Hz, 1H), 3.89 (td, J = 8.5, 6.5 Hz, 1H), 3.84 (d,J = 8.5 Hz, 1H), 3.67 (d, J = 1.0 Hz, 2H), 3.47 (d, J = 8.5 Hz, 1H),2.66 (s, 3H), 2.44 (d, J = 0.5 Hz, 3H), 1.76 (m, 1H), 1.24 (s, 3H). HRMS(ESI) MS m/z calcd for C₁₅H₂₁N₄OS [M + H]⁺ 305.1431, found 305.1425.Using (3-methyltetrahydrofuran-3- yl)methanamine. 16

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.04 (s, 1H), 6.77 (d, J = 0.5 Hz, 1H),3.77 (s, 2H), 2.67 (s, 3H), 2.45 (d, J = 0.5 Hz, 3H), 2.19-2.06 (m, 4H),1.78 (m, 1H), 1.65 (m, 1H). HRMS (ESI) MS m/z calcd for C₁₄H₁₉N₄OS [M +H]⁺ 291.1274, found 291.1266. Using 1-(aminomethyl)cyclobutanol. 17

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.05 (s, 1H), 6.89 (app s, 1H), 4.83(br d, J = 7.5 Hz, 2H), 4.48 (br d, J = 7.5 Hz, 2H), 2.64 (s, 3H), 2.47(d, J = 0.5 Hz, 3H), 1.78 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₄H₁₆N₅S[M + H]⁺ 268.1121, found 268.1119. Using3-methylazetidine-3-carbonitrile hydrochloride. 18

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.00 (s, 1H), 6.76 (app s, 1H), 4.33(br s, 4H), 3.71 (app t, J = 5.0 Hz, 4H), 2.65 (s, 3H), 2.44 (d, J = 0.5Hz, 3H), 1.90 (app t, J = 5.0 Hz, 4H). HRMS (ESI) MS m/z calcd forC₁₆H₂₁N₄OS [M + H]⁺ 317.1431, found 317.1422. Using7-oxa-2-azaspiro[3.5]nonane. 19

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.10 (s, 1H), 7.01 (d, J = 0.5 Hz, 1H),4.37-4.33 (m, 2H), 3.77 (ddd, J = 14.0, 8.5, 3.0 Hz, 2H), 3.11 (m, 1H),2.64 (s, 3H), 2.50 (d, J = 0.5 Hz, 3H), 2.18-2.13 (m, 2H), 2.04-1.98 (m,2H). HRMS (ESI) MS m/z calcd for C₁₅H₁₈N₅S [M + H]⁺ 300.1277, found300.1266. Using piperidine-4-carbonitrile. 20

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.00 (s, 1H), 6.77 (app s, 1H), 4.43(br s, 4H), 2.64 (s, 3H), 2.45 (d, J = 0.5 Hz, 3H), 1.58 (s, 3H). HRMS(ESI) MS m/z calcd for C₁₃H₁₇N₄OS [M + H]⁺ 278.1144, found 278.1139.Using 3-methylazetidin-3-ol hydrochloride. 21

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.03 (s, 1H), 6.76 (d, J = 0.5 Hz, 1H),4.75 (d, J = 6.0 Hz, 2H), 4.41 (d, J = 6.0 Hz, 2H), 3.81 (s, 2H), 2.67(s, 3H), 2.45 (d, J = 0.5 Hz, 3H), 1.42 (s, 3H). HRMS (ESI) MS m/z calcdfor C₁₄H₁₉N₄OS [M + H]⁺ 291.1274, found 291.1265. Using(3-methyloxetan-3- yl)methanamine. 22

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.02 (s, 1H), 6.75 (d, J = 0.5 Hz, 1H),4.36 (m, 1H), 4.03 (td, J = 11.0, 2.5 Hz, 2H), 3.62 (td, J = 11.0, 2.5Hz, 2H), 2.67 (s, 3H), 2.45 (d, J = 0.5 Hz, 3H), 2.11- 2.07 (m, 2H),1.77-1.76 (m, 2H). HRMS (ESI) MS m/z calcd for C₁₄H₁₉N₄OS [M + H]⁺291.1274, found 291.1268. Using tetrahydro-2H-pyran-4-amine. 23

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.99 (s, 1H), 6.73 (s, 1H), 4.26 (br s,4H), 2.63 (s, 3H), 2.43 (s, 3H), 1.39 (s, 6H). HRMS (ESI) MS m/z calcdC₁₄H₁₉N₄S [M + H]⁺ 275.1330, found 275.1332. Using 3,3-dimethylazetidinehydrochloride.

Preparation 248-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

A suspension of 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 25, 1.13 g, 5.01 mmol) in DCM (50 mL) was treated withmCPBA (77% w/w, 2.60 g, 11.57 mmol) at 0° C. and stirred whilst warmingto room temperature for 18 hours. The reaction was quenched with waterand extracted with DCM. The combined organic layers were washed withsaturated aqueous NaHCO₃ solution, dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 0-70% EtOAc in cyclohexane to afford the title compound(972 mg, 75%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 9.82 (s, 1H), 7.96 (d, J=0.5 Hz, 1H),3.54 (s, 3H), 2.78 (d, J=0.5 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₉H₉ClN₃O₂S [M+H]⁺ 258.0099, found 258.0092.

Preparation 25 8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine

A solution of 6-methyl-2-(methythio)pyrido[3,4-d]pyrimidin-8(7H)-one(Preparation 26, 100 mg, 0.483 mmol) in POCl₃ (5 mL) was heated to 70°C. for 1 hour. The reaction mixture was concentrated in vacuo. Theresidue was partitioned between EtOAc and washed with water, dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-20% EtOAc in cyclohexane toafford the title compound (28.4 mg, 52%).

¹H NMR (500 MHz, CDCl₃): δ ppm 9.16 (s, 1H), 7.43 (s, 1H), 2.75 (s, 3H),2.71 (s, 3H).

HRMS (ESI) MS m/z calcd for C₉H₉ClN₃S [M+H]⁺ 226.0206, found 226.0204.

Preparation 26 6-methyl-2-(methythio)pyrido[3,4-d]pyrimidin-8(7H)-one

To a solution of2-(methylthio)-5-(prop-1-yn-1-yl)pyrimidine-4-carboxamide (Preparation27, 270 mg, 1.303 mmol) in toluene (30 mL) was added pTSA (50 mg, 0.261mmol). The reaction mixture was heated to 90° C. for 18 hours. Thereaction mixture was concentrated in vacuo. The residue was dissolved inNH₃ in MeOH (7M, 10 mL) and heated to 80° C. for 18 hours. The reactionmixture was concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-5% MeOH in DCM to afford thetitle compound (150 mg, 56%).

Alternatively

A suspension of pentane-2,4-dione (5.10 mL, 49.7 mmol), copper iodide(487 mg, 2.56 mmol),5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide, (Preparation30, 8.00 g, 24.68 mmol) and Cs₂CO₃ (16.17 g, 49.6 mmol) in MeCN (70 mL)was heated to 85° C. for 18 hours. The reaction was treated with AcOH(70 mL) and AcONH₄ (28 g, 364 mmol) and heated to 85° C. for 5 hours.The reaction was partitioned between saturated aqueous NaHCO₃ and CHCl₃.The aqueous layers were extracted with CHCl₃. The combined organiclayers were washed with water and brine, dried (MgSO₄) and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluting with 20-100% EtOAc in cyclohexane followed by 0-20% MeOH inEtOAc to afford the title compound (3.22 g, 63%).

¹H NMR (500 MHz, CDCl₃): δ ppm 10.52 (br s, 1H), 8.91 (s, 1H), 6.28 (s,1H), 2.72 (s, 3H), 2.45 (s, 3H).

HRMS (ESI) MS m/z calcd for C₉H₁₀N₃SO [M+H]⁺ 208.0545, found 208.0550.

Preparation 27 2-(methylthio)-5-(prop-1-yn-1 yl)pyrimidine-4-carboxamide

A solution of methyl2-(methylthio)-5-prop-1-yn-1-yl)pyrimidine-4-carboxylate (Preparation28, 410 mg, 1.845 mmol) in NH₃ in MeOH (7M, 12 mL) was heated to 120° C.for 18 hours. The reaction mixture was concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with0-5% MeOH in DCM to afford the title compound (280 mg, 73%).

¹H NMR (500 MHz, CDCl₃): δ ppm 8.74 (s, 1H), 7.52 (br s, 1H), 5.61 (brs, 1H), 2.61 (s, 3H), 2.19 (s, 3H).

LCMS (ESI) Rt=1.87 minutes, MS m/z 208.27 [M+H]⁺

Preparation 28 Methyl 2-(methylthio)-5-prop-1-yn-1yl)pyrimidine-4-carboxylate

To a solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate(Preparation 29, 1.0 g, 3.80 mmol) in DMF (10 mL) was addedtributylpropynyl tin (1.4 mL, 4.56 mmol) and Pd(PPh₃)₄ (132 mg, 0.114mmol). The reaction mixture was heated to 110° C. under microwaveirradiation for 30 minutes. The reaction mixture was diluted with EtOAc,washed with saturated aqueous NaHCO₃ and water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 50-100% DCM in cyclohexane to afford thetitle compound (414 mg, 49%).

¹H NMR (500 MHz, CDCl₃): δ ppm 8.67 (s, 1H), 4.00 (s, 3H), 2.61 (s, 3H),2.14 (s, 3H).

HRMS (ESI) MS m/z calcd for C₉H₈N₂O₂S [M+H]⁺ 209.0379, found 209.038.

Preparation 29 Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate

A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (7.64g, 30.7 mmol) in MeOH (60 mL) was treated with sulfuric acid (2 mL) andheated to reflux for 24 hours. The mixture was poured onto ice water andextracted with DCM. The organic layer was washed with saturated aqueousNaHCO₃, dried (MgSO₄) and concentrated in vacuo to afford the titlecompound (6.42 g, 80%).

¹H NMR (500 MHz, CDCl₃): δ ppm 8.72 (s, 1H), 4.01 (s, 3H), 2.58 (s, 3H).

LCMS (ESI) Rt=2.35 minutes, MS m/z 263 [M+H]⁺

Preparation 30 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide

To a solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid(20.1 g, 81 mmol) in DCM (300 mL) was added catalytic DMF (1 drop) andoxalyl chloride (8.6 mL, 102 mmol) at 0° C. The reaction was stirred atroom temperature for 18 hours before concentrating in vacuo. The residuewas dissolved in DCM and treated with aniline (12 mL, 132 mmol) andtriethylamine (24 mL, 173 mmol) at 0° C. The reaction was stirred atroom temperature for 3 days. The reaction was quenched with 0.5M HCl andextracted with DCM. The combined organic layers were washed with waterand brine, dried (MgSO₄) and concentrated in vacuo to afford the titlecompound (24.91 g, 95%).

¹H NMR (500 MHz, CDCl₃): δ ppm 9.64 (br s, 1H), 8.86 (s, 1H), 7.75 (dd,J=8.6, 1.1 Hz, 2H), 7.42 (dd, J=8.5, 7.4 Hz, 2H), 7.22 (t, J=7.5 Hz,1H), 2.66 (s, 3H).

HRMS (ESI) MS m/z calcd for C₁₂H₁₁BrN₃OS [M+H]⁺ 325.9780, found325.9767.

Preparation 31N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)formamide

A solution of 2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)aniline(Preparation 52, 25 mg, 0.122 mmol) in formic acid (3 mL) was heated to100° C. for 1.5 hours. The reaction mixture was concentrated in vacuo.The residue was diluted with saturated aqueous NaHCO₃ and EtOAc. Theaqueous layer was re-extracted with DCM. The combined organic layerswere dried (MgSO₄) and concentrated in vacuo to afford the titlecompound (20 mg, 70%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.43 (d, J=8.5 Hz, 1H), 8.39 (s, 1H),7.83 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.14 (dd, J=8.5, 2.0 Hz, 1H), 4.13(s, 3H), 3.99 (s, 3H).

HRMS (ESI) MS m/z calcd for C₁₁H₁₃N₄O₂ [M+H]⁺ 233.1033, found 233.1032.

The following Preparations were prepared according to the methoddescribed for Preparation 31 using the appropriate aniline as describedbelow. Following concentration the residues were treated as above oraccording to one of the Purification Methods (PM) below:

Purification Method A: Azeotrope with toluene followed by silica gelcolumn chromatography eluting with 0-85% EtOAc in cyclohexane.Purification Method B: Azeotrope with toluene followed by silica gelcolumn chromatography eluting with 0-10% MeOH in DCMPurification Method C: Azeotrope with toluene followed by purified bysilica gel column chromatography eluting with 0-20% MeOH in DCM.Purification Method D: Further material was obtained by acidifying theaqueous layer with 0.5M HCl and extracting with DCM, drying (MgSO₄) andconcentrating in vacuo.

Preparation No Name/Structure Data 32

¹H NMR (500 MHz, Acetone-d₆): δ ppm 9.22 (br s, 1H), 8.55 (d, J = 8.5Hz, 1H), 8.52 (s, 1H), 8.36 (s, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.31 (dd,J = 8.5, 1.5 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.45 (t, J= 7.0 Hz, 3H). HRMS (ESI) MS m/z calcd for C₁₂H₁₆N₄O₂ [M + H]⁺ 247.1195,found 247.1195. Using 2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (Preparation 54). 33

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.35 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H),7.62 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.34 (dd, J = 8.3,1.8 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H). HRMS(ESI) MS m/z calcd for C₁₂H₁₄N₃O₂ [M + H]⁺ 232.1081, found 232.1079.Using 2-methoxy-4-(1-methyl-1H- pyrazol-3-yl)aniline (Preparation 45).PM A. 34

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.46 (d, J = 8.3 Hz, 1H), 8.41 (s, 1H),7.35 (dd, J = 11.4, 1.7 Hz, 2H), 7.25 (dd, J = 7.7, 1.7 Hz, 2H), 4.01(s, 3H), 3.86 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₂H₁₄N₃O₂ [M + H]⁺232.1081, found 232.1082. Using 2-methoxy-4-(1-methyl-1H-imidazol-2-yl)aniline (Preparation 46). PM B. 35

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.42-8.32 (m, 2H), 7.51 (d, J = 1.9 Hz,1H), 7.13(d, J = 1.8 Hz, 1H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 6.40 (d, J= 2.0 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H). HRMS (ESI) MS m/z calcd forC₁₂H₁₄N₃O₂ [M + H]⁺ 232.1081, found 232.1091. Using2-methoxy-4-(1-methyl-1H- pyrazol-5-yl)aniline (Preparation 47). PM A.36

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.43 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H),7.99 (d, J = 0.9 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.64 (dd, J = 8.4,1.8 Hz, 1H), 7.32 (d, J = 0.9 Hz, 1H), 4.03 (s, 3H). HRMS (ESI) MS m/zcalcd for C₁₁H₁₁N₂O₃ [M + H]⁺ 219.0764, found 219.0765. Using2-methoxy-4-(oxazol-2- yl)aniline (Preparation 48). PM A. 37

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.36 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H),7.05 (d, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.5, 1.5 Hz, 1H), 6.89 (s, 1H),3.96 (s, 3H), 3.59 (s, 3H), 2.43 (s, 3H). HRMS (ESI) MS m/z calcd forC₁₃H₁₆N₃O₂ [M + H]⁺ 246.1237, found 246.1233. Using4-(1,2-dimethyl-1H-imidazol-5- yl)-2-methoxyaniline (Preparation 53). PMD. 38

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.59-8.55 (m, 2H), 8.43 (s, 1H), 7.64(s, 1H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.01 (t, J = 72.8 Hz, 1H), 3.84(s, 3H). HRMS (ESI) MS m/z calcd for C₁₁H₁₁F₂N₄O₂ [M + H]⁺ 269.0850,found 269.0854. Using 2-(Difluoromethoxy)-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (Preparation 62). PM B. 39

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.53 (d, J = 8.4 Hz, 1H), 8.42 (s, 1H),7.48 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H), 4.23 (s, 3H),4.02 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₀H₁₂N₅O₂ [M + H]⁺ 234.0991,found 234.0992. Using 2-methoxy-4-(1-methyl-1H- tetrazol-5-yl)aniline(Preparation 49). PM A. 40

¹H NMR (500 MHz, MeOH-d4): δ ppm 8.35 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H),7.20 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 8.4, 1.9 Hz, 1H), 3.98 (s, 3H),2.48 (s, 3H), 2.36 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₃H₁₅N₂O₃ [M +H]⁺ 247.1082, found 247.1085. Using 4-(2,4-dimethyloxazol-5-yl)-2-methoxyaniline (Preparation 50). PM A. 41

LCMS (ESI) Rt = 0.50 minutes, MS m/z 246 [M + H]⁺. Using4-(1,5-dimethyl-1H-imidazol-2- yl)-2-methoxyaniline (Preparation 51). PMB. 42

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.47 (d, J = 8.3 Hz, 1H), 8.40 (s, 1H),7.33 (d, J = 1.8 Hz, 1H), 7.24 (dd, J = 8.3, 1.8 Hz, 1H), 4.00 (s, 3H),3.68 (s, 3H), 2.52 (s, 3H), HRMS (ESI) MS m/z calcd for C₁₂H₁₅N₄O₂ [M +H]⁺ 247.1195, found 247.1195 Using 4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-methoxyaniline (Preparation 61). PM C. 43

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.46 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H),7.30 (d, J = 1.7 Hz, 1H), 7.22 (dd, J = 8.2, 1.7 Hz, 1H), 4.24 (q, J =7.0 Hz, 2H), 3.68 (s, 3H), 2.52 (s, 3H), 1.51 (t, J = 7.0 Hz, 3H). HRMS(ESI) MS m/z calcd for C₁₃H₁₇N₄O₂ [M + H]⁺ 261.1352, found 261.1345.Using 4-(4,5-dimethyl-4H-1,2,4-triazol- 3-yl)-2-ethoxyaniline(Preparation 59). PM B. 44

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.65 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H),8.43 (s, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.22 (dd, J = 8.0, 1.7 Hz, 1H),4.26- 4.19 (m, 4H), 1.51 (t, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H).HRMS (ESI) MS m/z calcd for C₁₃H₁₇N₄O₂ [M + H]⁺ 261.1352, found 261.1352Using 2-ethoxy-4-(4-ethyl-4H-1,2,4- triazol-3-yl)aniline (Preparation60). PM C.

Preparation 45 2-methoxy-4-(1-methyl-1H-pyrazol-3-yl)aniline

To a solution of2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (310mg, 1.244 mmol) and 3-bromo-1-methyl-1H-pyrazole (154 mg, 0.957 mmol) inTHF (3 mL) was added Pd(dppf)Cl₂.DCM (40 mg, 0.049 mmol) and 2M aqueousNa₂CO₃ (1 mL) and the reaction was heated to 65° C. for 18 hours. Thereaction was diluted with EtOAc and water. The aqueous layer wasextracted with EtOAc, the combined organic layers were washed with waterand brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 0-60% EtOAc incyclohexane to afford the title compound (34 mg, 18%).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.33 (d, J=18.8 Hz, 2H), 7.28 (d, J=1.2Hz, 2H), 7.20 (d, J=7.9 Hz, 1H), 6.74 (dd, J=7.9, 1.2 Hz, 1H), 6.45 (dd,J=2.2, 1.2 Hz, 1H), 3.95 (m, 6H), 3.85 (br s, 2H).

HRMS (ESI) MS m/z calcd for C₁₁H₁₄N₃O [M+H]⁺ 204.1131, found 204.1141.

The following Preparations were prepared according to the methoddescribed for Preparation 45 using the appropriate aniline andheterocycle as described below. The crude reaction residues werepurified as above or according to one of the following PurificationMethods (PM):

Purification Method A: Silica gel column chromatography eluting with0-5% MeOH in DCM.Purification Method B: Silica gel column chromatography eluting with0-15% EtOAc in cyclohexane.Purification Method C: Silica gel column chromatography eluting with0-10% MeOH in DCM.

Preparation No Name/Structure Data 46

¹H NMR (500 MHz, CDCl₃): δ ppm 7.18 (d, J = 1.8 Hz, 1H), 7.10 (d, J =1.3 Hz, 1H), 6.99 (dd, J = 8.0, 1.8 Hz, 1H), 6.95 (s, 1H), 6.76 (d, J =8.0 Hz, 1H), 3.98 (br s, 2H), 3.92 (s, 3H), 3.75 (s, 3H). HRMS (ESI) MSm/z calcd for C₁₁H₁₄N₃O [M + H]⁺ 204.1131, found 204.1139. Using2-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)aniline and2-bromo-1-methyl-1H- imidazole at 110° C. under microwave irradiation.PM A. 47

¹H NMR (500 MHz, CDCl₃): δ ppm 7.51 (d, J = 1.9 Hz, 1H), 6.86 (dd, J =7.9, 1.8 Hz, 1H), 6.83 (s, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.26 (d, J =1.9 Hz, 1H), 3.98 br (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H). HRMS (ESI) MSm/z calcd for C₁₁H₁₄N₃O [M + H]⁺ 204.1131, found 204.1140. Using4-bromo-2-methoxyaniline and 1-methyl-1H-pyrazol-5-ylboronic acid withPd(PPh₃)₄ at 70° C. 48

¹H NMR (500 MHz, CDCl₃): δ ppm 7.65 (d, J = 0.8 Hz, 1H), 7.57-7.49 (m,2H), 7.19 (d, J = 0.9 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.11 (br s,2H), 3.96 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₀H₁₁N₂O₂ [M + H]⁺191.0815, found 191.0825. Using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline and 2-bromooxazolehydrochloride with Pd(PPh₃)₄ at 110° C. under microwave irradiation. PMB. 49

¹H NMR (500 MHz, CDCl₃): δ ppm 7.31 (d, J = 1.8 Hz, 1H), 7.11 (dd, J =8.0, 1.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.21 (br s, 2H), 4.18 (s,3H), 3.94 (s, 3H). HRMS (ESI) MS m/z calcd for C₉H₁₂N₅O [M + H]⁺206.1042, found 206.1046. Using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline and 5-bromo-1-methyl-1H-tetrazole. 50

¹H NMR (500 MHz, CDCl₃): δ ppm 7.04-6.97 (m, 2H), 6.76 (d, J = 8.5 Hz,1H), 3.93 (s, 5H), 2.47 (s, 3H), 2.35 (s, 3H). HRMS (ESI) MS m/z calcdfor C₁₂H₁₅N₂O₂ [M + H]⁺ 219.1133, found 219.1128. Using2-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)aniline and5-bromo-2,4- dimethyloxazole. 51

LCMS (ESI) Rt = 0.87 minutes, MS m/z 218 [M + H]⁺. Using2-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)aniline and2-bromo-1,5-dimethyl- 1H-imidazole with Pd(PPh₃)₄ at 100 ° C. undermicrowave irradiation. PM C.

Preparation 52 2-methoxy-4-(1-methyl-1H-1,2,3-triazol-5-yl)aniline

A suspension of2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (122mg, 0.490 mmol), 5-iodo-1-methyl-1H-1,2,3-triazole (93 mg, 0.445 mmol),CsF (203 mg, 1.335 mmol) and Pd(PPh₃)₄ (51.4 mg, 0.045 mmol) in DME/MeOH(3:1, 4 mL) was heated to 150° C. for 1 hour under microwaveirradiation. The reaction mixture was filtered and purified by silicagel column chromatography eluting with 50-70% EtOAc in cyclohexane toafford the title compound (75 mg, 83%).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.67 (s, 1H), 6.85-6.84 (m, 2H), 6.80 (d,J=1.5 Hz, 1H), 4.06 (s, 3H), 3.91 (s, 3H).

HRMS (ESI) MS m/z calcd for C₁₀H₁₃N₄O [M+H]⁺ 205.1084, found 205.1093.

Preparation 53 4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyaniline

A suspension of2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (925mg, 3.71 mmol), 5-bromo-1,2-dimethylimidazole (650 mg, 3.71 mmol), CsF(1.7 g, 11.14 mmol) and Pd(PPh₃)₄ (86 mg, 0.074 mmol) in DME/MeOH (2:1,18 mL) was heated to 150° C. for 10 minutes under microwave irradiation.The reaction mixture was diluted with EtOAc and water. The aqueous layerwas basified by addition of 2M aqueous Na₂CO₃ and extracted with EtOAc.The combined organic layers were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by reverse phase columnchromatography eluting with 100% water to afford the title compound (800mg, 99%).

¹H NMR (500 MHz, MeOH-d₄) δ ppm 6.84 (d, J=2.0 Hz, 1H), 6.81 (s, 1H),6.78 (d, J=2.0 Hz, 1H), 6.75 (s, 1H), 3.88 (s, 3H), 3.53 (s, 3H), 2.41(s, 3H).

HRMS (ESI) MS m/z calcd for C₁₂H₁₆N₃O [M+H]⁺ 218.1288, found 218.1200.

Preparation 54 2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline

To a solution 3-(3-ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole(Preparation 55, 748 mg 3.19 mmol) in EtOH (50 mL) was added 10% Pd/C(130 mg, 0.123 mmol). The reaction was stirred in an atmosphere ofhydrogen (1 atm) at room temperature for 18 hours. The reaction mixturewas filtered through Celite and concentrated in vacuo to afford thetitle compound (539 mg, 83%).

¹H NMR (500 MHz, MeOH-d₄) δ ppm 8.49 (s, 1H), 7.15 (d, J=2.0 Hz, 1H),7.08 (dd, J=8.0, 2.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.15 (q, J=7.0 Hz,2H), 3.80 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₁H₁₄N₄O [M+H]⁺ 249.0988, found 249.0992.

Preparation 55 3-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole

To a cooled (0° C.) suspension of5-(3-ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol(Preparation 56, 1.16 g 4.14 mmol) in DCM (11.8 mL) was added a solutionof 35% hydrogen peroxide (0.91 mL, 12.2 mmol) in acetic acid (6 mL)dropwise. The reaction was stirred at room temperature for 70 minutes.DCM (50 mL) was added followed by 2M NaOH (48 mL) to obtain a neutralpH. The aqueous layer was extracted with DCM. The combined organiclayers were dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 5-10% EtOH inDCM to afford the title compound (607 mg, 60%).

¹H NMR (500 MHz, DMSO-d₆): δ ppm 8.66 (s, 1H), 8.03 (d, J=8.5 Hz, 1H),7.65 (d, J=1.6 Hz, 1H), 7.47 (dd, J=1.6, 8.5 Hz, 1H), 4.31 (q, J=7.3 Hz,2H), 3.81 (s, 3H), 1.36 (t, J=6.9 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₁H₁₃N₄O₃ [M+H]⁺ 249.0988, found 249.0985.

Alternatively

To a suspension of 3-ethoxy-N-methyl-4-nitrobenzamide (Preparation 58,609 mg, 2.72 mmol) in DCE (12 mL) was added thionyl chloride (0.79 mL,10.86 mmol). The mixture was stirred at 90° C. under microwaveirradiation for 3 hours. The reaction mixture was concentrated in vacuoand the resulting orange oil was dried in vacuo for 1 hour. Formylhydrazide (196 mg, 3.26 mmol) in DMF (10 mL) was added and the reactionheated at 110° C. under microwave irradiation for 1 hour. Brine wasadded to the reaction mixture. The resulting precipitate was filtered,washed with water and dried in vacuo to afford the title compound (290mg, 43%).

Preparation 565-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol

To a solution of 3-ethoxy-4-nitrobenzohydrazide (Preparation 57, 1287 mg5.72 mmol) in THF (26 mL) was added a solution of methyl isothiocyanate(422 mg 5.78 mmol) in THF (5 mL). Triethylamine (102 uL, 0.71 mmol) wasadded and the reaction was stirred at room temperature for 22 hours. Thereaction was concentrated in vacuo and the residue dissolved in 1 M NaOH(85 mL). The reaction was stirred at 45° C. for 2.5 hours. The reactionwas filtered through Celite and the filtrate extracted with ether. Theaqueous was acidified using concentrated HCl and extracted with EtOAc.The combined organic layer was washed with water and brine, dried(Na₂SO₄) and concentrated in vacuo to afford the title compound (1.16 g,72%).

¹H NMR (500 MHz, DMSO-d₆): δ ppm 14.11 (brs, 1H), 8.03 (d, J=8.5 Hz,1H), 7.66 (d, J=1.6 Hz, 1H), 7.44 (dd, J=1.9, 8.5 Hz, 1H), 4.29 (q,J=6.9 Hz, 2H), 3.56 (s, 3H), 1.35 (t, J=6.9 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₁H₁₂N₄O₃S [M+H]⁺ 475.2570, found 475.2571.

Preparation 57 3-Ethoxy-4-nitrobenzohydrazide

To a cooled (0° C.) solution of 3-ethoxy-4-nitrobenzoic acid (PCT IntAppl. 2008003958, 1.06 g, 5.02 mmol) in THF (10 mL) and triethylamine(0.86 mL, 6.1 mmol) was added ethyl chloroformate (0.56 mL, 5.85 mmol)dropwise. The reaction was stirred at 0° C. for 15 minutes. Hydrazinehydrate (1.27 mL, 26 mmol) was added in one portion and the reactionstirred for 5 minutes and then at room temperature for 1 hour. Thereaction was concentrated in vacuo, partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic layer was washed with brine, dried(Na₂SO₄) and concentrated in vacuo to afford the title compound (1.07 g,95%).

¹H NMR (500 MHz, DMSO-d₆): δ ppm 10.05 (br s, 1H, NH), 7.92 (d, J=8.3Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.51 (dd, J=8.3, 1.7 Hz, 1H), 4.70 (brs, 2H), 4.27 (q, J=6.9 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₉H₁₁N₃O₄ [M+H]⁺ 226.0822, found 226.0828.

Preparation 58 3-Ethoxy-N-methyl-4-nitrobenzamide

To a suspension of 3-ethoxy-4-nitrobenzoic acid (PCT Int Appl.2008003958, 2.57 g, 12.2 mmol), methanamine hydrochloride (1.32 g, 19.5mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (3.73 g, 24.4 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (4.67 g, 24.4 mmol) in DCM (50 mL) was addedN-ethyl-N-isopropylpropan-2-amine (10.6 mL, 60.9 mmol). The resultingsolution was stirred at room temperature for 18 hours. The organic phasewas washed with water, citric acid solution, saturated aqueous NaHCO₃and brine, dried (Na₂SO₄) and concentrated in vacuo to afford the titlecompound (2.41 g, 88%).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.83 (d, J=8.3 Hz, 1H), 7.60 (d, J=1.7Hz, 1H), 7.25 (dd, J=8.3, 1.7 Hz, 1H), 6.23 (s, broad, 1H), 4.26 (q,J=7.0 Hz, 2H), 3.05 (d, J=4.9 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H).

LCMS (ESI) Rt=1.09 minutes, MS m/z 225 [M+H]⁺.

Preparation 59 4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyaniline

To a solution of 4-bromo-2-ethoxyaniline (150 mg, 0.694 mmol) in toluene(2 ml) in a microwave vial was added 3,4-dimethyl-triazole (135 mg, 1.39mmol), Pd(OAc)₂ (16 mg, 0.069 mmol), K₂CO₃ (585 mg, 4.23 mmol), pivalicacid (47 mg, 0.458 mmol) and PCy₃.HBF₄ (51 mg, 0.139 mmol). The reactionwas flushed with nitrogen, sealed and heated to 110° C. for 18 hours.The reaction mixture was concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 0-20% MeOH in EtOAc toafford the title compound (51 mg, 32%).

¹H NMR (500 MHz, MeOH-d₄) 7.08 (d, J=1.7 Hz, 1H), 7.02 (dd, J=8.0, 1.7Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.64 (s, 3H),2.49 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₂H₁₇N₄O [M+H]⁺ 233.1402, found 233.1402.

Preparation 60 2-ethoxy-4-(4-ethyl-4H-1,2,4-triazol-3-yl)aniline

To a solution of 4-bromo-2-ethoxyaniline (75 mg, 0.347 mmol) in toluene(1 ml) in a microwave vial was added 4-ethyl-4H-1,2,4-triazole (50 mg,0.521 mmol), Pd(OAc)₂ (8 mg, 0.035 mmol), K₂CO₃ (293 mg, 2.12 mmol),pivalic acid (23 mg, 0.229 mmol) and PCy₃.HBF₄ (26 mg, 0.069 mmol). Thereaction was flushed with nitrogen, sealed and heated to 110° C. for 18hours. The reaction mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 0-20% MeOH inEtOAc to afford the title compound (51 mg, 63%).

¹H NMR (500 MHz, MeOH-d₄): δ ppm 8.57 (s, 1H), 7.08 (d, J=1.8 Hz, 1H),7.01 (dd, J=8.0, 1.8 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.20-4.11 (m, 4H),1.47 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.2 Hz, 3H).

LCMS (ESI) Rt=1.04 minutes, MS m/z 263.0838 [M+H]⁺.

Alternatively

To a solution of 3-(3-ethoxy-4-nitrophenyl)-4-ethyl-4H-1,2,4-triazole(Preparation 63, 410 mg, 1.563 mmol) in EtOH (25 ml) was added 10% Pd/C(83 mg, 0.078 mmol). The reaction was stirred in an atmosphere ofhydrogen (1 atm) at room temperature for 18 hours. 10% Pd/C (83 mg,0.078 mmol) was added and the reaction mixture stirred in an atmosphereof hydrogen for a further 24 hours. The reaction mixture was filteredthrough Celite, washed with EtOH and concentrated in vacuo to afford thetitle compound (280 mg, 77%).

The following Preparations were prepared according to the methoddescribed for Preparation 59 using the appropriate aniline andheterocycle as described below. The crude reaction residues werepurified as above or according to one of the following PurificationMethods (PM): Purification Method A: Silica gel column chromatographyeluting with 0-7% MeOH in EtOAc.

Preparation No Name/Structure Data 61

¹H NMR (500 MHz, MeOH-d₄): δ ppm 7.10 (d, J = 1.7 Hz, 1H), 7.02 (dd, J =8.0, 1.7 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H),2.49 (s, 3H). HRMS (ESI) MS m/z calcd for C₁₁H₁₅N₄O [M + H]⁺ 219.1246,found 219.1252. Using 4-bromo-2-methoxyaniline and3,4-dimethyl-triazole. 62

LCMS (ESI) Rt = 1.07 minutes, MS m/z 241 [M + H]⁺. Using 4-bromo-2-(difluoromethoxy)aniline and 4-methyl- 4H-1,2,4-triazole. PM A.

Preparation 63 3-(3-ethoxy-4-nitrophenyl)-4-ethyl-4H-1,2,4-triazole

To a cooled (0° C.) suspension of5-(3-ethoxy-4-nitrophenyl)-4-ethyl-4H-1,2,4-triazole-3-thiol(Preparation 64, 1.0 g, 3.40 mmol) in DCM (11.5 ml) was added a solutionof 35% hydrogen peroxide (1.0 ml, 10.19 mmol) in acetic acid (4.67 ml,82 mmol) dropwise. The reaction was stirred at room temperature for 3hours. DCM (12 ml) was added, followed by 1 M NaOH to obtain a neutralpH. The aqueous layer was re-extracted with DCM. The combined organiclayers were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 0-10% MeOH inDCM to afford the title compound (410 mg, 46%).

¹H NMR (500 MHz, MeOH-d₄) δ ppm 8.73 (s, 1H), 7.97 (d, J=8.1 Hz, 1H),7.57 (d, J=1.7 Hz, 1H), 7.37 (dd, J=8.1, 1.7 Hz, 1H), 4.30 (q, J=6.9 Hz,2H), 4.24 (q, J=7.4 Hz, 2H), 1.47 (t, J=6.9 Hz, 3H), 1.43 (t, J=7.4 Hz,3H).

HRMS (ESI) MS m/z calcd for C₂H₄BrN₄ [M+H]⁺ 162.9619, found 162.9640.

Preparation 645-(3-ethoxy-4-nitrophenyl)-4-ethyl-4H-1,2,4-triazole-3-thiol

To a solution of 3-ethoxy-4-nitrobenzohydrazide (Preparation 57, 1.5 g,6.66 mmol) in THF (32 ml) was added ethyl isothiocyanate (1.0 ml, 11.32mmol), followed by triethylamine (0.11 ml, 0.799 mmol). The reactionmixture was stirred at room temperature for 18 hours. Ethylisothiocyanate (2 ml, 22.64 mmol) added and the reaction stirred for afurther 24 hours. Ethyl isothiocyanate (2 ml, 22.64 mmol) added and thereaction stirred for a further 72 hours. The reaction was concentratedin vacuo and the residue redissolved in 1M NaOH (15 ml). The reactionwas stirred at 45° C. for 4 hours. The reaction was filtered throughCelite and the filtrate extracted with ether. The aqueous layer wasacidified with 1 M HCl and extracted with EtOAc. The combined organiclayer was washed with water and brine, dried (MgSO₄) and concentrated invacuo to afford the title compound (1.0 g, 51%).

¹H NMR (500 MHz, MeOH-d₄) δ ppm 7.96 (d, J=8.2 Hz, 1H), 7.56 (d, J=1.6Hz, 1H), 7.37 (dd, J=8.2, 1.6 Hz, 1H), 4.29 (q, J=6.9 Hz, 2H), 4.21 (q,J=7.0 Hz, 2H), 1.47 (t, J=6.9 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₂H₁₅N₄O₃S [M+H]⁺ 295.0865, found 295.0857.

Preparation 65 5-bromo-1-methyl-1H-tetrazole

A suspension of zinc bromide (1.20 g, 5.33 mmol) and1-methyl-1H-tetrazole-5-thiol (302 mg, 2.60 mmol) in AcOH (6 mL) washeated to 40° C. When homogeneous, AcOOH (39% w/w in AcOH, 2.65 mL,15.64 mmol) was added. The resulting mixture was heated to 80° C. for 18hours. The reaction was diluted with water, NaHCO₃ (solid) was addeduntil pH 6/7 was reached and the resulting solution was extracted withEtOAc. The combined organics were washed with 1M Na₂SO₃, saturatedaqueous NaHCO₃, water and brine, dried (MgSO₄) and concentrated in vacuoto afford the title compound (276 mg, 65%).

¹H NMR (500 MHz, CDCl₃): δ ppm 4.10 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂H₄BrN₄ [M+H]⁺ 162.9619, found 162.9640.

Preparation 66 3-ethyl-3-methoxyazetidine hydrochloride

A solution of 1-benzhydryl-3-ethyl-3-methoxyazetidine (Preparation 68,340 mg, 1.208 mmol) was dissolved in acetonitrile (8 mL), treated with1-chloroethyl chloroformate (175 μL, 1.628 mmol) at 0° C. and thenrefluxed for 1 hour. The mixture was concentrated in vacuo, redissolvedin MeOH (8 mL) and refluxed for 1.5 hours. The solution was concentratedin vacuo, the residue dissolved in water (8 mL) and washed withcyclohexane twice. The aqueous layer was concentrated in vacuo andco-evaporated with EtOH (three times) and DCM (twice) to afford thetitle compound (173 mg, 95%).

¹H NMR (500 MHz, DMSO-d₆): δ ppm 9.29 (br s, 1H), 9.17 (br s, 1H), 3.83(br s, 2H), 3.73 (br s, 2H), 3.13 (s, 3H), 1.84 (q, J=7.3 Hz, 2H), 0.77(t, J=7.3 Hz, 3H).

The following Preparation was prepared according to the method describedfor Preparation 66 using the appropriate azetidine as described below.The crude reaction residue was purified as above.

Prep- aration No Name/Structure Data 67

¹H NMR (500 MHz, DMSO- d₆): δ ppm 9.25 (br s, 1H), 9.07 (br s, 1H),3.91-3.82 (m, 2H), 3.80-3.68 (m, 2H), 3.39 (q, J = 7.0 Hz, 2H), 1.46 (s,3H), 1.12 (t, J = 7.0 Hz, 3H). Using 1-benzhydryl-3-ethoxy-3-methylazetidine (Preparation 69).

Preparation 68 1-benzhydryl-3-ethyl-3-methoxyazetidine

A solution of 1-benzhydryl-3-ethylazetidin-3-ol (Preparation 70, 490 mg,1.833 mmol) in DMF (10 mL) was cooled to 0° C., treated with sodiumhydride (60% w/w in mineral oil, 115 mg, 2.88 mmol) and stirred at roomtemperature for 90 minutes. The mixture was cooled to 0° C., treatedwith methyl iodide (150 μL, 2.41 mmol) and stirred at room temperaturefor 2.5 hours. The reaction was quenched with water and extracted withEtOAc. The combined organics were washed with water and brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-5% EtOAc in cyclohexane toafford the title compound (347 mg, 67%).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.42 (m, 4H), 7.32-7.26 (m, 4H),7.23-7.17 (m, 2H), 4.42 (s, 1H), 3.17 (s, 3H), 3.16-3.12 (m, 2H), 3.00(d, J=8.6 Hz, 2H), 1.88 (q, J=7.4 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₉H₂₄NO [M+H]⁺ 282.1858, found 282.1860.

The following Preparation was prepared according to the method describedfor Preparation 68 using the appropriate azetidinol and alkylatingreagent as described below. The crude reaction residue was purified asabove.

Preparation No Name/Structure Data 69

¹H NMR (500 MHz, CDCl₃): δ ppm 7.47-7.39 (m, 4H), 7.31-7.24 (m, 4H),7.22-7.14 (m, 2H), 4.41 (s, 1H), 3.37 (q, J = 7.0 Hz, 2H), 3.18-3.09 (m,2H), 3.03-2.92 (m, 2H), 1.54 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H). HRMS(ESI) MS m/z calcd for C₁₉H₂₄NO [M + H]⁺ 282.1858, found 282.1845. Using1-benzhydryl-3-methylazetidin- 3-ol (Preparation 71) and ethyl bromideat room temperature for 18 hours.

Preparation 70 1-benzhydryl-3-ethylazetidin-3-ol

A solution of 1-benzhydrylazetidin-3-one (500 mg, 2.107 mmol) in THF (10mL) was treated with EtMgCl (2M in THF, 2.2 ml, 4.40 mmol) at 0° C. andstirred at room temperature for 1 hour. The mixture was quenched withsaturated aqueous NH₄Cl and extracted with EtOAc. The combined organicswere washed with water and brine, dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 0-20% EtOAc in cyclohexane to afford the title compound(492 mg, 87%).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.50-7.37 (m, 4H), 7.32-7.25 (m, 4H),7.25-7.15 (m, 2H), 4.39 (s, 1H), 3.23 (d, J=8.9 Hz, 2H), 2.97 (d, J=8.8Hz, 2H), 1.93 (s, 1H), 1.83 (q, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₁₈H₂₂NO [M+H]⁺ 268.1701, found 268.1699.

The following Preparation was prepared according to the method describedfor Preparation 70 using the appropriate magnesium reagent as describedbelow. The crude reaction residue was purified as above.

Preparation No Name/Structure Data 71

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.36 (m, 4H), 7.32-7.24 (m, 4H),7.22-7.16 (m, 2H), 4.37 (s, 1H), 3.23- 3.18 (m, 2H), 3.01-2.97 (m, 2H),1.97 (br s, 1H), 1.54 (s 3H). HRMS (ESI) MS m/z calcd for C₁₇H₂₀NO [M +H]⁺ 254.1545, found 254.1553. Using MeMgBr (3M in Et₂O)

1-8. (canceled)
 9. A compound selected from:(S)—N8-(3,3-dimethylbutan-2-yl)-N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine,

andN2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine,

or a pharmaceutically acceptable salt or solvate thereof. 10-11.(canceled)
 12. A pharmaceutical composition comprising a compoundaccording to claim 9, or a pharmaceutically acceptable salt or solvatethereof, in admixture with a pharmaceutically acceptable diluent orcarrier.
 13. A method of treating a proliferative disorder in a patientin need of such treatment, said method comprising administering to saidpatient a therapeutically effective amount of a compound according toclaim 9, or a pharmaceutically acceptable salt or solvate thereof. 14.The method of claim 13, wherein the proliferative condition is cancer.15. (canceled)
 16. A compound according to claim 9, wherein saidcompound isN2-(4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-2-ethoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine,

or a pharmaceutically acceptable salt thereof.
 17. A compound accordingto claim 9, wherein said compound is(S)—N8-(3,3-dimethylbutan-2-yl)-N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine,

or a pharmaceutically acceptable salt thereof.